• animal model;
  • autoimmune disorders;
  • cancer;
  • diabetes;
  • oncogene;
  • post-translational modification;
  • protein phosphorylation;
  • signal transduction;
  • transgenic mice;
  • tumour suppressor


  1. Top of page
  2. Abstract
  3. Reversible tyrosine phosphorylation
  4. PTP function: animal models lead the way
  5. Knockout intercrosses: less is more
  6. Customizing PTP expression
  7. Oncogenic as well as tumour-suppressive PTPs
  8. PTPs in the immune system
  9. Attractive new ways to address PTP function
  10. Conclusion
  11. Acknowledgements
  12. References

Some 40-odd genes in mammals encode phosphotyrosine-specific, ‘classical’ protein tyrosine phosphatases. The generation of animal model systems and the study of various human disease states have begun to elucidate the important and diverse roles of protein tyrosine phosphatases in cellular signalling pathways, development and disease. Here, we provide an overview of those findings from mice and men, and indicate several novel approaches that are now being exploited to further our knowledge of this fascinating enzyme family.




protein tyrosine phosphatase


receptor-type PTP

Reversible tyrosine phosphorylation

  1. Top of page
  2. Abstract
  3. Reversible tyrosine phosphorylation
  4. PTP function: animal models lead the way
  5. Knockout intercrosses: less is more
  6. Customizing PTP expression
  7. Oncogenic as well as tumour-suppressive PTPs
  8. PTPs in the immune system
  9. Attractive new ways to address PTP function
  10. Conclusion
  11. Acknowledgements
  12. References

Research on how oncoviruses transform mammalian cells has led to the firm establishment of the tyrosine-specific phosphorylation of cellular proteins as a key signalling mechanism to evoke essential cell decisions, for example proliferation and differentiation. Many viral oncogenes have, in fact, been found to represent hyperactive mutants of protein tyrosine kinases found in the genome and thus distort the delicate phosphotyrosine balance within cells. Protein tyrosine phosphatases (PTPs), by virtue of their ability to counteract the activity of kinases, were therefore expected to have tumour-suppressive powers. Several years after the identification and isolation of PTPs, their catalytic activities were found to exceed those of kinases by log orders of magnitude. This led to the view that PTP enzymes represent housekeeping ‘kinase counteractors’ that, in isolation, display limited substrate selectivity. Since then, many specific defects have been found to be attributable to mutations in distinct PTP genes, highlighting that catalytic behaviour in the test tube cannot easily be extrapolated to PTP functioning within the live cell. Nowadays, protein tyrosine kinases and PTPs are regarded as corporate enzymes that coordinate the regulation of signalling responses, sometimes even by acting in concert. Here, we review current knowledge on the physiological roles of the classical, phosphotyrosine-specific PTPs (Fig. 1) as derived from studies of mammalian pathologies or the use of animal models. In particular, we discuss the novel roads taken to deepen our understanding of this enzyme family, as well as their growing involvement in human pathologies, strengthening their nomination as desirable drug targets. We refer to other minireviews in this series [1–3] for a discussion of the regulatory principles and structure–function relationships displayed by classical and dual-specificity tyrosine phosphatases.


Figure 1.  Schematic depiction of the domain composition for all subfamilies of classical phosphotyrosine-specific PTPs. Each of the 38 classical mammalian PTP genes is represented by a single protein isoform. PTP subtypes, according to Andersen et al. [11], are listed. Please note that because of, for example alternative splicing, a single PTP gene may encode multiple isoforms, sometimes including receptor-like and non-transmembrane enzymes (hence the R7 subtype classification for cytosolic KIM-containing PTPs). In addition, specific isoforms within subtype families may contain additional protein domains and/or targeting sequences (e.g. the ER anchoring tail in PTP1B and the nuclear localization signal in TCPTP) [6,96]. Domain abbreviations: BRO1, baculovirus BRO homology 1; CA, carbonic anhydrase-like; Cad, cadherin-like; CRB, cellular retinaldehyde-binding protein-like; D1 and D2, membrane-proximal and membrane distal PTP domains, respectively (enzymatically active domains are in green, PTP domains with reduced or even no activity are in bluish green); FERM, band 4.1/ezrin/radixin/moesin homology (in blue); FN, fibronectin type-III repeat-like (orange ovals); HD, His domain; Ig, immunoglobulin-like; KIM, kinase interaction motif (light blue); KIND, kinase N-lobe-like domain; MAM, meprin/A2/RPTPμ homology; PDZ, postsynaptic density-95/discs large/ZO1 homology; Pro, proline-rich sequence; SH2, src homology 2 (in yellow). Adapted from Alonso et al. [9] and Andersen et al. [10].

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PTP function: animal models lead the way

  1. Top of page
  2. Abstract
  3. Reversible tyrosine phosphorylation
  4. PTP function: animal models lead the way
  5. Knockout intercrosses: less is more
  6. Customizing PTP expression
  7. Oncogenic as well as tumour-suppressive PTPs
  8. PTPs in the immune system
  9. Attractive new ways to address PTP function
  10. Conclusion
  11. Acknowledgements
  12. References

Because of their high enzymatic activity and usually very low endogenous expression levels, many researchers have found that ectopic expression of PTPs in cell models can lead to off-target effects. Quite a number of PTPs, for example, were able to dephosphorylate the activated insulin receptor when tested in overexpression systems [4]. By contrast, in vivo studies have pointed to PTP1B, and to a lesser extend TCPTP and SHP1, as being responsible for down-tuning the insulin-induced signals at the receptor level [5,6]. Not infrequently, PTP overexpression appeared incompatible with cell survival, frustrating attempts to generate stably transfected cell lines [7] and leading to faulty implications in apoptosis. Because it is still unclear which residues within a catalytic PTP domain structure actually contribute to substrate-specificity profiles [8], predicting PTP involvement in signalling networks on the basis of sequence information is currently not an option. Therefore, given the scarce knowledge on relevant ligands and substrates and the experimental drawbacks of overexpression in cell models, insight into the physiological role of individual phosphatases has come mostly from loss-of-function animal studies.

In Table 1 functional data based on transgenic (knockout) mouse models and/or mutations as identified in human pathologies are listed for all classical PTP genes. For some PTPs, such information has not yet been obtained, and occasionally functional clues that come from other types of studies are included (in parentheses). Please note that both the mammalian PTP gene nomenclature [9] and the PTP subtype indication [10,11] suggest a clear subdivision between receptor-type and non-receptor-type encoding ones. Such a distinction, however, is somewhat artificial because several PTP genes, e.g. PTPN5 [12], PTPRE [13], PTPRQ [14] and PTPRR [15], give rise to both receptor-type and non-transmembrane PTP isoforms by means of an alternative use of promoters, splice sites and AUG start codons, or due to proteolytic processing. Table 1 illustrates that the construction of knockout mouse models, via homologous recombination in embryonic stem cells, for the different PTP genes is rapidly nearing completion. The phenotypes obtained all advocate the importance of PTP signalling. PTP loss has lethal consequences during early embryonic development or results in no or only mild effects, presumably reflecting redundancy as a safeguard for the organism.

Table 1.   Phosphotyrosine-specific class I PTP-related phenotypes in mouse and human.
Gene symbolProtein namePTP typeaMouse modelHuman/mouse/rat phenotype description (functional evidence from other sources)Ref
  1. a PTP types according to Andersen et al. [11]. Phenotypic consequences of mutations in human (H), mouse (M) or rat (R) are given. In absence of such information, the functional data derived from cell models are mentioned between brackets and aligned to the right. b NOP (no obvious phenotype): normal and healthy appearance, normal breeding and behaviour. c The apparently conflicting phenotypes reflect different mouse mutants. See text for explanation.

PTPN1PTP1BNT1YesM: NOPb– Increased insulin sensitivity, obesity resistance[6,96]
PTPN2TCPTPNT1YesM: Die 3–5 weeks postpartum; defective haematopoiesis and immune function[6,96]
PTPN3PTPH1NT5YesM: Enhanced growth due to augmented GH signalling, normal haematopoietic functions[97,98]
PTPN4PTP-MEG1NT5M: Involved in motor learning and cerebellar synaptic plasticity[99]
PTPN5STEPR7(duration of ERK signalling in the brain, neuronal plasticity)[94,100,101]
PTPN6SHP1NT2YesM: Die within first month; haematopoietic defects, splenomegaly, autoimmune disease, osteoporosis, increased insulin sensitivity H: Candidate tumour suppressor in lymphomas[5,46,48,102] [103]
PTPN7HePTPR7YesM: NOP (suppresses ERK activation)[104]
PTPN9PTP-MEG2NT3YesM: Embryonic lethal; defective secretory vesicle function[105]
PTPN11SHP2NT2YesM: Lethal at preimplantation stage; defective cell survival signalling H: Mutated in Noonan syndrome and Leopard syndrome[51,106] [107]
PTPN12PTP-PESTNT4YesM: Embryonic lethal; regulator of cell motility H: CD2BP1, a PTP-PEST binding protein, is mutated in PAPA syndrome[108] [83]
PTPN13PTPBASNT7YesM: NOP – Impaired regenerative neurite outgrowth, negative regulator of STAT signalling (control of oocyte meiotic maturation)[109–111]
PTPN14PTP36NT6YesM: Androgenization of female mice (US Patent 20020152493) (negative regulator of cell motility)[112]
PTPN18BDPNT4(involved in HER2 signal attenuation)[113]
PTPN20TypPTPNT9(regulator of actin cytoskeleton dynamics)[114]
PTPN21PTPD1NT6(modulator of Tec family kinases and Stat3 activity)[115]
PTPN22LYPNT4YesM: Enhanced immune functions, splenomegaly, lymphadenopathy. H: Gain of function mutant causes autoimmune diseases[81] [82]
PTPN23HD-PTPNT8(candidate tumour suppressor on 3p21.3; regulates endothelial migration via FAK)[116] [117]
PTPRARPTPαR4YesM: NOP – affected neuronal migration and synaptic plasticity, learning deficit, decreased anxiety, impaired NCAM-mediated neurite elongation[34,35,118–120]
PTPRBVE-PTPR3YesM: Embryonic lethal, reduced vascular development, heterozygotes are normal[121,122]
PTPRCCD45R1YesM: No T cells, immature B cells, impaired differentiation of oligodendrocyte precursor cells, dysmyelination[123,124]
PTPRDRPTPδR2AYesM: Impaired learning and memory, retarded growth, early mortality, posture and motor defects[39]
PTPRERPTPεR4YesM: NOP – Hypomyelination, defective osteoclast functioning, reduced src activity, aberrant macrophage function[36,74,125,126]
PTPRFLARR2AYesM: NOP – Mammary gland defect, altered neuronal circuitry, learning deficits, enhanced IGF-1 signaling[44,127–129]
PTPRGRPTPγR5YesM: NOP (tumor suppressor candidate on 3p14)[33] [130,131]
PTPRHSAP1R3(negatively regulates cell motility)[132]
PTPRJDEP-1R3YescM: NOP / Die at mid gestation with severe defects in vascular organization H: frequently deleted in human cancers[16,17] [19–24]
PTPRKRPTPκR2BYesM: NOP R: defective thymocyte development (tumor suppressor candidate on 6q22-23)[42] [133] [134]
PTPRMRPTPμR2BYesM: NOP – Reduced dilatation in mesenteric arteries[135,136]
PTPRNIA-2R8YesM: NOP- Glucose intolerance, defective insulin secretion[26]
PTPRN2IA-2βR8YesM: NOP – Glucose intolerance, impaired insulin secretion[25]
PTPROGLEPP1R3YesM: Reduced renal filtration surface area (tumour suppressor candidate in lung and hepatocellular carcinomas and CLL)[137] [138]
PTPRQPTPS31R3YesM: Impaired development of cochlear hair bundles (inositol lipid phosphatase activity)[139] [63]
PTPRRPTPRRR7YesM: Hyperphosphorylated ERK in brain, locomotive impairment[140]
PTPRSRPTPσR2AYesM: Decreased brain size, pituitary dysplasia, defects in olfactory lobes, enhanced nerve regeneration, ulcerative colitis of the gut[141–148]
PTPRTRPTPρR2BH: Mutated in colon cancer specimen (associates with cadherin complexes, dephosphorylates STAT3)[64,65] [149,150]
PTPRURPTPλR2B(associates with cadherin complexes, dephosphorylates β-catenin)[151]
PTPRVOST-PTPR3YesM: Increased susceptibility to chemically induced tumours, increased perinatal lethality, hypoglycaemia, beta cell hyperproliferation (mediator of p53-induced cell cycle arrest)[152,153] [154]
PTPRZRPTPζR5YesM: NOP – Remyelination defects, impaired learning, resistant to Helicobacter pylori-induced gastric ulcers[32,155,156]

For the mouse gene Ptprj it may seem that conflicting reports are listed in Table 1, but this reflects the two different ways in which the mouse models were created. Mice carrying a DEP-1 null mutation, caused by replacing of exons 3–5 within the Ptprj locus with a β-galactosidase–neomycin phosphotransferase fusion cassette, have not revealed any phenotypic consequences [16]. However, transgenic mice in which the intracellular catalytic domain of DEP-1 was replaced by the enhanced green fluorescent protein displayed an embryonic lethal phenotype because of vascularization failure, disorganized vascular structures and cardiac defects [17]. Apparently, the remaining extracellular portion of the DEP-1 molecule in the latter model acts as a functional ligand that blocks the pathways responsible for the correct assembly of endothelial cells during angiogenesis. Indeed, the relevance of DEP-1 extracellular segment-derived signals for endothelial-cell growth and angiogenesis was recently corroborated in wild-type mice by administration of a bivalent mAb against the DEP-1 ectodomain that resulted in clustering and activation of the phosphatase [18]. Mapping of a colon-cancer-susceptibility locus in mice and investigations into human tumour types pointed to potential tumour-suppressor activity for DEP-1 [19–24]. However, no spontaneous tumour development has been observed in DEP-1-deficient mice [16], indicating that additional genetic alterations may be required for tumours to arise and urging for studies on the susceptibility to experimentally induced cancers in this mouse model.

Knockout intercrosses: less is more

  1. Top of page
  2. Abstract
  3. Reversible tyrosine phosphorylation
  4. PTP function: animal models lead the way
  5. Knockout intercrosses: less is more
  6. Customizing PTP expression
  7. Oncogenic as well as tumour-suppressive PTPs
  8. PTPs in the immune system
  9. Attractive new ways to address PTP function
  10. Conclusion
  11. Acknowledgements
  12. References

To overcome the hurdle of redundancy within the PTP family, cross-breeding of different PTP mutant mouse strains, especially within the respective subfamilies (Fig. 1), has recently been taken up. The receptor-type 8 (R8; nomenclature according to Andersen et al. [11]) PTPs IA-2 and IA-2β, for example, are enzymatically inactive transmembrane proteins that localize in dense core vesicles of neuroendocrine cells, including pancreatic insulin-producing beta cells. Single knockout mice revealed subtle defects in insulin secretion and, consequently, in the regulation of blood glucose levels [25,26]. Double knockouts, completely devoid of R8 PTPs, appeared normal and healthy but showed clear glucose intolerance and an absent first-phase insulin-release curve compared with wild-type mice [27]. In addition, female double-knockout mice were essentially infertile due to impaired luteinizing hormone secretion from dense core vesicles in pituitary cells [28]. These findings, and comparable observations in Caenorhabditis elegans [29], show that IA-2 and IA-2β cooperate in the first-phase release of hormones from neuroendocrine cells. Because R8 PTPs are enzymatically inactive, their mode of action may reflect phosphotyrosine-dependent protein binding, much like the SH2 and PTB protein domains [30], rather than dephosphorylation. Elegant work in cell models provided an intriguing two-way mode of action in which a ‘substrate-binding’ PTP combines phosphorylation-dependent and -independent protein interactions to regulate the secretory activity of exocrine cells in response to metabolic demands [31]. Secretory stimuli were found to induce the release of dense core vesicles and their subsequent exocytosis via calpain-mediated cleavage of IA-2, which immobilizes these granules onto the submembranous cytoskeleton. The resulting IA-2 cytoplasmic tail subsequently moves into the nucleus and enhances secretory granule gene expression by binding and protecting STAT5 phosphotyrosines.

For the R4 (RPTPα and RPTPε) and R5 (RPTPγ and RPTPζ) receptor-type PTPs the individual knockout strains lack obvious phenotypes [32–36]. Perhaps RPTPα/RPTPε and RPTPγ/RPTPζ double-knockout mice will shed more light on the role of these enzymes. To date, studies on RPTPα/RPTPε double-knockout mice have revealed that the R4 PTPs display significant differences in their regulation of Kv channels and the tyrosine kinase Src [37] and, thus, that sequence similarity does not necessarily imply functional redundancy in vivo. By contrast, intercrossing of RPTPδ and RPTPσ knockout mice yielded double-knockout animals that were paralysed, did not breathe and died shortly after birth by caesarean section [38]. These mice exhibited extensive muscle dysgenesis and spinal cord motoneuron loss, demonstrating that these R2A-type PTPs are functionally redundant with respect to appropriate motoneuron survival and axon targeting in mammals [38]. This predicts that the generation and study of mice that lack all three R2A PTPs (LAR, RPTPδ and RPTPσ) are rather daunting tasks with a likely ‘embryonic lethal’ outcome. Crossing of LAR mutant mice with either RPTPδ- or RPTPσ-deficient mice may prove informative. The phenotype of mice with a combined deficiency for LAR and RPTPσ phosphatase activity is currently under study (N. Uetani and M. Tremblay, personal communication). Investigating the joint functions of LAR and PTPδ would be of interest in the synaptic field, given that each has been shown to play a role in synaptic plasticity and memory [39,40]. Other RPTPs may also play roles in synapse dynamics [35,41]. Unfortunately, the genes encoding LAR and RPTPδ (Ptprf and Ptprd) both map on mouse chromosome 4, some 20 cM apart. Thus, to obtain alleles that harbour mutations in these two R2A-type genes, an extensive breeding programme of double-heterozygous animals or a laborious double knockout at the ES cell stage would be required. It should be noted that current LAR mutant mouse models, lines ST534 [42] and LARΔP [43], do not represent full null alleles [44] and may express trace amounts of wild-type [45] or truncated [43] protein, respectively.

Customizing PTP expression

  1. Top of page
  2. Abstract
  3. Reversible tyrosine phosphorylation
  4. PTP function: animal models lead the way
  5. Knockout intercrosses: less is more
  6. Customizing PTP expression
  7. Oncogenic as well as tumour-suppressive PTPs
  8. PTPs in the immune system
  9. Attractive new ways to address PTP function
  10. Conclusion
  11. Acknowledgements
  12. References

Multiple mutant mouse models are available for the two cytosolic SH2 domain-containing PTPs, SHP1 and SHP2 (Table 1). SHP1-deficient mice, provided by a naturally occurring point mutation in the so-called motheaten (me) strain, die within the first month after birth [46–48]. Motheaten viable (mev) mice contain a more limited inactivation of the gene and have a less severe phenotype. Likewise, both the first generation of SHP2 knockout animals [49,50], which resulted in the expression of N-terminally truncated SHP2 mutants, and the recent full null mouse model [51] were incompatible with life. SHP1 is expressed mainly in haematopoietic cells and SHP2 displays a rather ubiquitous profile [52]. The lethal phenotypes of SHP-deficient animals encouraged the use of novel in vivo approaches to study their physiological function; in recent years several conditionally defective SHP alleles have been developed [51,53–56] through the use of tissue- or developmental-stage-specific recombination strategies [57]. Also, the strategy of overexpressing a dominant-negative SHP2 mutant in specific tissues has been exploited [58]. In conjunction with work on cell models, these studies demonstrated that SHP2 is required for optimal activation of Ras-Erk growth factor signalling cascades; however, key substrates of this PTP remain to be discovered [52,59]. The identification of inherited dominant autosomal mutations in the SHP2-encoding gene PTPN11 as a major cause of Noonan syndrome, a disease manifested by short stature, congenital heart defects and facial abnormalities, pointed for the first time to the detrimental effect of SHP2 hyperactivity [60]. Noonan syndrome is associated with an increased risk for developing leukaemia, and somatic mutations of PTPN11 that result in hyperactivation of SHP2 have been identified in sporadic cases of juvenile myelomonocytic leukaemia and childhood acute lymphoblastic leukaemia [59,60]. Such mutations have also been detected, albeit at low frequency, in solid tumours. Thus, SHP2 should, in fact, be viewed as the product of a genuine proto-oncogene. Intriguingly, SHP2 hypoactivity leads to a disease as well: Leopard syndrome [60]. The clinical features of Noonan and Leopard syndromes largely overlap, thus providing a mechanistic conundrum. Recent studies on SHP2 function and the identification of other genes involved in developmental syndromes related to Noonan and Leopard begin to provide a picture in which developmental processes depend heavily on a very narrow bandwidth of MAPK signal strength; MAPK activities that are either below or above this range would result in comparable phenotypes [61].

Oncogenic as well as tumour-suppressive PTPs

  1. Top of page
  2. Abstract
  3. Reversible tyrosine phosphorylation
  4. PTP function: animal models lead the way
  5. Knockout intercrosses: less is more
  6. Customizing PTP expression
  7. Oncogenic as well as tumour-suppressive PTPs
  8. PTPs in the immune system
  9. Attractive new ways to address PTP function
  10. Conclusion
  11. Acknowledgements
  12. References

Led by the original belief that as counteractors of oncogenic protein tyrosine kinases the PTPs would function as tumour suppressors, the search for mutations in PTP genes was taken up rapidly following their initial discovery. However, despite the mapping of several PTP genes in genomic regions that are frequently deleted in human tumours, such an anti-cancer link never progressed beyond the ‘association’ to the ‘causal’ level. By contrast, a major tumour suppressor has been successfully identified among the dual-specific phosphatases: PTEN (see the accompanying minireview by Pulido and Hooft van Huijsduijnen [2]). PTEN’s tumour-suppressive action, however, is primarily attributable to its lipid phosphatase activity [62]. Interestingly, one of the classical PTP genes, PTPRQ, encodes an inositol lipid phosphatase [63]; undoubtedly research groups are searching for altered PTPRQ function in tumour specimens. In an impressive mutational analysis of 83 different tyrosine phosphatase genes in human cancer specimens [64], the PTPRQ gene did not emerge as a hot spot for mutations. Rather, 26% of the colon cancer cases and a smaller fraction of lung, breast and gastric cancers were found to have mutations in one of no fewer than six, classic phosphotyrosine-specific genes: PTPRF, PTPRG, PTPRT, PTPN3, PTPN13 and PTPN14. The most commonly mutated PTP gene was PTPRT and reintroduction of PTPRT in human cancer cells inhibited cell growth [64]. It therefore came as a surprise that in another cohort study, hardly any mutations in PTPRT were encountered [65], weakening a possible critical role for PTPRT mutations in cancer development. Additional studies of this subject are clearly warranted.

As mentioned previously, various lines of evidence point to the DEP-1-encoding gene PTPRJ as a tumour-suppressor gene, especially in colon cancer [19–24]. DEP-1 mutations were not identified in the tyrosine phosphatome study [64] mentioned above, but because the common DEP-1 lesions in cancer specimens reflect allelic loss rather than point mutations or small insertions/deletions this may well be due to the experimental design. Irrespective, DEP-1-deficient mice did not show an increase in tumour incidence [16]. This may well reflect the accepted paradigm that tumorigenesis depends on multiple genetic alterations acting in concert; the tumour-suppressive powers of PTPs may require the context of additional specific genetic defects, possibly in other PTP genes, to become noticeable. For example, RPTPδ has been highlighted recently as a potential target for microdeletions in lung cancer, cutaneous squamous cell carcinomas and neuroblastomas [66–68].

A recent experiment that underscores the need for further genetic lesions, involved the crossing of PTP1B deficiency onto a p53 null background in mice [69]. PTP1B/p53 double-knockouts displayed decreased survival rates compared with mice lacking p53 alone, due to an increased development of B-cell lymphomas. This is in line with the observation that PTP1B null mice have increased numbers of B cells in bone marrow and lymph nodes. Thus, in a p53-null background, PTP1B determines the latency and type of tumour development via its role in B-cell development. Bearing in mind this ‘anti-oncogenic effect’ of PTP1B, one might have expected a similar outcome from the crossing of PTP1B null mice with transgenic mice prone to develop breast cancer due to mutations in ErbB2. By contrast, two groups found that the absence of PTP1B actually delays ErbB2-induced tumour formation considerably and significantly reduces the incidence of lung metastases in these animal models [70,71]. Thus, although the mechanism is unclear [72], PTP1B supports ErbB2 signalling in these mouse tumour models, thereby joining SHP2 in the dubious honour of being an ‘oncogenic’ PTP. Several lines of evidence also indicate that RPTPε harbours tumour-promoting activity. Expression of RPTPε is upregulated in mouse mammary tumours induced by ErbB2 or Ras, and transgenic mice that overexpress this PTP in their mammary epithelium developed mammary hyperplasia and often solitary mammary tumours [73]. Cells derived from ErbB2-induced mammary tumours in RPTPε-deficient mice were less transformed than cells expressing PTPε [73,74]. RPTPε exerts is effect by activating Src in ErbB2-induced mammary tumours [74,75] and provides a necessary, but insufficient, signal for oncogenesis. For further discussions on the potential oncogenic role of PTPs, including RPTPα, SAP1, LAR, SHP1 and HePTP, see Östman et al. [76].

PTPs in the immune system

  1. Top of page
  2. Abstract
  3. Reversible tyrosine phosphorylation
  4. PTP function: animal models lead the way
  5. Knockout intercrosses: less is more
  6. Customizing PTP expression
  7. Oncogenic as well as tumour-suppressive PTPs
  8. PTPs in the immune system
  9. Attractive new ways to address PTP function
  10. Conclusion
  11. Acknowledgements
  12. References

Because immunological processes intrinsically require the cooperative action of many different cells, tissues and even organs, it is not surprising that the use of animal models has been crucial in elucidating PTP involvement in these matters [77–79]. The motheaten mouse strains, which carry mutations in SHP1, provided a first example of an autoimmune disease caused by defective PTP signalling [47,48]. Autoimmune diseases were subsequently reported for mice that express a CD45 gain-of-function mutant [80] or lack LYP expression [81]. These latter two PTPs have also been found to be associated with human diseases. CD45 abnormalities have been detected in some severe combined immunodeficiency patients and in T cells from patients with systemic lupus erythematosus [77]. More recently, a polymorphism in the LYP-encoding gene PTPN22 was linked to a range of human autoimmune disorders including type 1 diabetes, rheumatoid arthritis, Graves’ disease, generalized vitiligo and systemic lupus erythematosus [82]. The polymorphism markedly affects the binding of LYP to its partner-in-crime CSK, resulting in impaired downregulation of T-cell receptor signals and thus an increased risk of hyper-reactive T cells mounting a destructive immune response against autoantigens. A similar situation is encountered in the autoinflammatory disorder PAPA syndrome (pyogenic sterile arthritis, Pyoderma gangrenosum and acne) where mutations in CD2BP1 severely reduce its binding to PTP-PEST [83]. Consequently, the suppressive effect normally exerted by the CD2BP1/PTP-PEST complex on CD2-mediated T-cell activation is impaired and inflammation cannot be properly controlled.

Attractive new ways to address PTP function

  1. Top of page
  2. Abstract
  3. Reversible tyrosine phosphorylation
  4. PTP function: animal models lead the way
  5. Knockout intercrosses: less is more
  6. Customizing PTP expression
  7. Oncogenic as well as tumour-suppressive PTPs
  8. PTPs in the immune system
  9. Attractive new ways to address PTP function
  10. Conclusion
  11. Acknowledgements
  12. References

Molecular and mechanistic information on the position of PTPs within cellular signalling pathways has also been obtained through exploitation of cell lines derived from knockout animals. For example, the use of mouse embryonic fibroblasts derived from various PTP-deficient strains enabled a ‘physiological search’ for negative regulators of PDGF beta receptor signalling [84]. The study underscored that ‘in cellulo’ PTPs do display extensive site selectivity in their action on tyrosine kinase receptors, a characteristic that is often lost when studied in the test tube. The increasing use of RNAi technology [85] to effectively reduce PTP protein levels is a powerful alternative, especially if functional redundancy needs to be taken into account.

Novel ways to interfere with PTP action at the protein level are also being explored. Synthesis of small molecule PTP inhibitors has gained significant priority given the exciting discoveries on PTP1B biology. However, thus far, it has proved quite difficult to achieve proper PTP specificity for such molecules, preferably combined with good cell penetrability and biodistribution. Intriguingly, the application of interfering peptides to study PTP function has also gained momentum. As discussed in the accompanying review by den Hertog et al. [1], several RPTPs contain a wedge-shaped helix–loop–helix region just N-terminal of their first, catalytically active PTP domain that, upon RPTP dimerization, can inhibit enzyme function by blocking entrance to the catalytic site of the opposing RPTP subunit [86,87]. Taking this knowledge one step further, Longo and co-workers recently demonstrated that the administration of cell-penetrable wedge-domain peptides does affect cellular signalling processes in a PTP-specific way, providing an alternative strategy to inhibit PTPs [88]. A subset of RPTPs dimerize via interactions mediated by their single-pass transmembrane segment [89] which may potentially influence their activity [90]. Therefore, reminiscent of the wedge peptide strategy, the design of peptides that target transmembrane helices [91] may well provide complementary peptide tools to manipulate RPTP signalling. Importantly, since transcellular signalling via dimerization-dependent ligand binding to the RPTP ectodomains may be at stake [92] such peptides may influence both intracellular and extracellular signalling pathways. Reasoning along these lines, the future identification of RPTP ligands and the mapping of their binding sites on RPTP ectodomains may yield additional peptide tools to fine-tune RPTP signalling, much like the in vivo exploitation of an antibody recognizing the extracellular domain of DEP-1 [18]. Further support for this approach has come from studies of a small homophilic peptide derived from LAR ectodomain, which appears to activate the enzyme [93]. In addition, short peptides screened for affinity to PTPσ ectodomains can block ligand interactions and alter neurite outgrowth in culture (Stoker and Hawadle, unpublished). Furthermore, for some applications, one may even envisage turning to the in situ application of complete PTP mutant domains [94,95].

These novel approaches to modulate PTP signalling in live cells leave untouched the daunting task of identifying the actual partner proteins and substrates with which PTPs interact. Rapid progress in isolation of native protein complexes, for example, by exploiting tandem affinity purification protocols and the selective enrichment of phosphoprotein-containing proteins, and in their subsequent identification by dedicated mass spectrometric means should therefore be exploited to provide a wealth of information on the signalling nodes involving PTPs within the coming years. Furthermore, the power of modern proteomics should also help uncover PTP targets after analysis of changes in total cellular tyrosine phosphoprotein profiles in various knockout animals and cell lines.


  1. Top of page
  2. Abstract
  3. Reversible tyrosine phosphorylation
  4. PTP function: animal models lead the way
  5. Knockout intercrosses: less is more
  6. Customizing PTP expression
  7. Oncogenic as well as tumour-suppressive PTPs
  8. PTPs in the immune system
  9. Attractive new ways to address PTP function
  10. Conclusion
  11. Acknowledgements
  12. References

We have come a long way in recognizing the impact of reversible tyrosine phosphorylation on cell fate, tissue development and health, and the contribution of protein tyrosine phosphatases to these matters, not in the least by exploiting animal models with PTP-specific deficiencies. To date, the data underscore the importance of investigating PTP action under close-to-physiological conditions. By and large, the mouse data correlate well with observations from human disease states, corroborating the value of these animal models in uncovering the aetiology of human diseases. The advent of novel approaches to manipulate PTP activity now enables careful design of functional studies in cell models. Most notably, boosted by PTP1B’s modulatory effect in diabetes, obesity and cancer, and LYP’s involvement in multiple autoimmune diseases, we are bound to expect major advances regarding the development of specific, cell-penetrable small molecule inhibitors or agonists in the upcoming years, serving both the research community and public health.


  1. Top of page
  2. Abstract
  3. Reversible tyrosine phosphorylation
  4. PTP function: animal models lead the way
  5. Knockout intercrosses: less is more
  6. Customizing PTP expression
  7. Oncogenic as well as tumour-suppressive PTPs
  8. PTPs in the immune system
  9. Attractive new ways to address PTP function
  10. Conclusion
  11. Acknowledgements
  12. References

We thank Frank Böhmer, Rob Hooft van Huijsduijnen and Arne Östman for critical reading of the manuscript, and Noriko Uetani and Michel Tremblay for sharing information prior to publication. We apologize to all colleagues whose original work could not be referred to due to space constraints. We are grateful to Yvet Noordman for preparation of Fig. 1. This work was supported in part by European Research Community Funds (HPRN-CT-2000-00085 and MRTN-CT-2006-035830).


  1. Top of page
  2. Abstract
  3. Reversible tyrosine phosphorylation
  4. PTP function: animal models lead the way
  5. Knockout intercrosses: less is more
  6. Customizing PTP expression
  7. Oncogenic as well as tumour-suppressive PTPs
  8. PTPs in the immune system
  9. Attractive new ways to address PTP function
  10. Conclusion
  11. Acknowledgements
  12. References
  • 1
    den Hertog J, Östman A & Böhmer F-D (2008) Protein tyrosine phosphatases: regulatory mechanisms. FEBS J 275, 831847.
  • 2
    Pulido R & Hooft van Huijsduijnen R (2008) Protein tyrosine phosphatases: dual-specificity phosphatases in health and disease. FEBS J 275, 848866.
  • 3
    Tabernero L, Aricescu A, Jones E & Szedlacsek S (2008) Protein tyrosine phosphatases: structure–function relationships. FEBS J 275, 867882.
  • 4
    Asante-Appiah E & Kennedy BP (2003) Protein tyrosine phosphatases: the quest for negative regulators of insulin action. Am J Physiol Endocrinol Metab 284, E663E670.
  • 5
    Dubois MJ, Bergeron S, Kim HJ, Dombrowski L, Perreault M, Fournes B, Faure R, Olivier M, Beauchemin N, Shulman GI et al. (2006) The SHP-1 protein tyrosine phosphatase negatively modulates glucose homeostasis. Nat Med 12, 549556.
  • 6
    Dube N & Tremblay ML (2005) Involvement of the small protein tyrosine phosphatases TC-PTP and PTP1B in signal transduction and diseases: from diabetes, obesity to cell cycle, and cancer. Biochim Biophys Acta 1754, 108117.
  • 7
    Cuppen E, Wijers M, Schepens J, Fransen J, Wieringa B & Hendriks W (1999) A FERM domain governs apical confinement of PTP-BL in epithelial cells. J Cell Sci 112, 32993308.
  • 8
    Tiganis T & Bennett AM (2007) Protein tyrosine phosphatase function: the substrate perspective. Biochem J 402, 115.
  • 9
    Alonso A, Sasin J, Bottini N, Friedberg I, Friedberg I, Osterman A, Godzik A, Hunter T, Dixon J & Mustelin T (2004) Protein tyrosine phosphatases in the human genome. Cell 117, 699711.
  • 10
    Andersen JN, Mortensen OH, Peters GH, Drake PG, Iversen LF, Olsen OH, Jansen PG, Andersen HS, Tonks NK & Moller NPH (2001) Structural and evolutionary relationship among protein tyrosine phosphatase domains. Mol Cell Biol 21, 71177136.
  • 11
    Andersen JN, Jansen PG, Echwald SM, Mortensen OH, Fukada T, Del Vecchio R, Tonks NK & Moller NP (2004) A genomic perspective on protein tyrosine phosphatases: gene structure, pseudogenes, and genetic disease linkage. FASEB J 18, 830.
  • 12
    Bult A, Zhao F, Dirkx R Jr, Sharma E, Lukacsi E, Solimena M, Naegele JR & Lombroso PJ (1996) STEP61: a member of a family of brain-enriched PTPs is localized to the endoplasmic reticulum. J Neurosci 16, 78217831.
  • 13
    Elson A & Leder P (1995) Identification of a cytoplasmic, phorbol ester-inducible isoform of protein tyrosine phosphatase epsilon. Proc Natl Acad Sci USA 92, 1223512239.
  • 14
    Seifert RA, Coats SA, Oganesian A, Wright MB, Dishmon M, Booth CJ, Johnson RJ, Alpers CE & Bowen-Pope DF (2003) PTPRQ is a novel phosphatidylinositol phosphatase that can be expressed as a cytoplasmic protein or as a subcellularly localized receptor-like protein. Exp Cell Res 287, 374386.
  • 15
    Chirivi RGS, Dilaver G, van de Vorstenbosch R, Wanschers B, Schepens J, Croes H, Fransen J & Hendriks W (2004) Characterization of multiple transcripts and isoforms derived from the mouse protein tyrosine phosphatase gene Ptprr. Genes Cells 9, 919933.
  • 16
    Trapasso F, Drusco A, Costinean S, Alder H, Aqeilan RI, Iuliano R, Gaudio E, Raso C, Zanesi N, Croce CM et al. (2006) Genetic ablation of Ptprj, a mouse cancer susceptibility gene, results in normal growth and development and does not predispose to spontaneous tumorigenesis. DNA Cell Biol 25, 376382.
  • 17
    Takahashi T, Takahashi K, St John PL, Fleming PA, Tomemori T, Watanabe T, Abrahamson DR, Drake CJ, Shirasawa T & Daniel TO (2003) A mutant receptor tyrosine phosphatase, CD148, causes defects in vascular development. Mol Cell Biol 23, 18171831.
  • 18
    Takahashi T, Takahashi K, Mernaugh RL, Tsuboi N, Liu H & Daniel TO (2006) A monoclonal antibody against CD148, a receptor-like tyrosine phosphatase, inhibits endothelial-cell growth and angiogenesis. Blood 108, 12341242.
  • 19
    Ruivenkamp CA, van Wezel T, Zanon C, Stassen AP, Vlcek C, Csikos T, Klous AM, Tripodis N, Perrakis A, Boerrigter L et al. (2002) Ptprj is a candidate for the mouse colon-cancer susceptibility locus Scc1 and is frequently deleted in human cancers. Nat Genet 31, 295300.
  • 20
    Ruivenkamp C, Hermsen M, Postma C, Klous A, Baak J, Meijer G & Demant P (2003) LOH of PTPRJ occurs early in colorectal cancer and is associated with chromosomal loss of 18q12-21. Oncogene 22, 34723474.
  • 21
    Iuliano R, Le Pera I, Cristofaro C, Baudi F, Arturi F, Pallante P, Martelli ML, Trapasso F, Chiariotti L & Fusco A (2004) The tyrosine phosphatase PTPRJ/DEP-1 genotype affects thyroid carcinogenesis. Oncogene 23, 84328438.
  • 22
    Lesueur F, Pharoah PD, Laing S, Ahmed S, Jordan C, Smith PL, Luben R, Wareham NJ, Easton DF, Dunning AM et al. (2005) Allelic association of the human homologue of the mouse modifier Ptprj with breast cancer. Hum Mol Genet 14, 23492356.
  • 23
    van Puijenbroek M, Dierssen JW, Stanssens P, van Eijk R, Cleton-Jansen AM, van Wezel T & Morreau H (2005) Mass spectrometry-based loss of heterozygosity analysis of single-nucleotide polymorphism loci in paraffin embedded tumors using the MassEXTEND assay: single-nucleotide polymorphism loss of heterozygosity analysis of the protein tyrosine phosphatase receptor type J in familial colorectal cancer. J Mol Diagn 7, 623630.
  • 24
    Luo L, Shen GQ, Stiffler KA, Wang QK, Pretlow TG & Pretlow TP (2006) Loss of heterozygosity in human aberrant crypt foci (ACF), a putative precursor of colon cancer. Carcinogenesis 27, 11531159.
  • 25
    Kubosaki A, Gross S, Miura J, Saeki K, Zhu M, Nakamura S, Hendriks W & Notkins AL (2004) Targeted disruption of the IA-2beta gene causes glucose intolerance and impairs insulin secretion but does not prevent the development of diabetes in NOD mice. Diabetes 53, 16841691.
  • 26
    Saeki K, Zhu M, Kubosaki A, Xie J, Lan MS & Notkins AL (2002) Targeted disruption of the protein tyrosine phosphatase-like molecule IA-2 results in alterations in glucose tolerance tests and insulin secretion. Diabetes 51, 18421850.
  • 27
    Kubosaki A, Nakamura S & Notkins AL (2005) Dense core vesicle proteins IA-2 and IA-2beta: metabolic alterations in double knockout mice. Diabetes 54(Suppl 2), S46S51.
  • 28
    Kubosaki A, Nakamura S, Clark A, Morris JF & Notkins AL (2006) Disruption of the transmembrane dense core vesicle proteins IA-2 and IA-2beta causes female infertility. Endocrinology 147, 811815.
  • 29
    Cai T, Fukushige T, Notkins AL & Krause M (2004) Insulinoma-associated protein IA-2, a vesicle transmembrane protein, genetically interacts with UNC-31/CAPS and affects neurosecretion in Caenorhabditis elegans. J Neurosci 24, 31153124.
  • 30
    Seet BT, Dikic I, Zhou MM & Pawson T (2006) Reading protein modifications with interaction domains. Nat Rev Mol Cell Biol 7, 473483.
  • 31
    Ort T, Voronov S, Guo J, Zawalich K, Froehner SC, Zawalich W & Solimena M (2001) Dephosphorylation of beta2-syntrophin and Ca2+/mu-calpain-mediated cleavage of ICA512 upon stimulation of insulin secretion. EMBO J 20, 40134023.
  • 32
    Harroch S, Palmeri M, Rosenbluth J, Custer A, Okigaki M, Shrager P, Blum M, Buxbaum JD & Schlessinger J (2000) No obvious abnormality in mice deficient in receptor protein tyrosine phosphatase beta. Mol Cell Biol 20, 77067715.
  • 33
    Lamprianou S, Vacaresse N, Suzuki Y, Meziane H, Buxbaum JD, Schlessinger J & Harroch S (2006) Receptor protein tyrosine phosphatase gamma is a marker for pyramidal cells and sensory neurons in the nervous system and is not necessary for normal development. Mol Cell Biol 26, 51065119.
  • 34
    Ponniah S, Wang DZ, Lim KL & Pallen CJ (1999) Targeted disruption of the tyrosine phosphatase PTPalpha leads to constitutive downregulation of the kinases Src and Fyn. Curr Biol 9, 535538.
  • 35
    Petrone A, Battaglia F, Wang C, Dusa A, Su J, Zagzag D, Bianchi R, Casaccia-Bonnefil P, Arancio O & Sap J (2003) Receptor protein tyrosine phosphatase alpha is essential for hippocampal neuronal migration and long-term potentiation. EMBO J 22, 41214131.
  • 36
    Peretz A, Gil-Henn H, Sobko A, Shinder V, Attali B & Elson A (2000) Hypomyelination and increased activity of voltage-gated K(+) channels in mice lacking protein tyrosine phosphatase epsilon. EMBO J 19, 40364045.
  • 37
    Tiran Z, Peretz A, Sines T, Shinder V, Sap J, Attali B & Elson A (2006) Tyrosine phosphatases epsilon and alpha perform specific and overlapping functions in regulation of voltage-gated potassium channels in Schwann cells. Mol Biol Cell 17, 43304342.
  • 38
    Uetani N, Chagnon MJ, Kennedy TE, Iwakura Y & Tremblay ML (2006) Mammalian motoneuron axon targeting requires receptor protein tyrosine phosphatases sigma and delta. J Neurosci 26, 58725880.
  • 39
    Uetani N, Kato K, Ogura H, Mizuno K, Kawano K, Mikoshiba K, Yakura H, Asano M & Iwakura Y (2000) Impaired learning with enhanced hippocampal long-term potentiation in PTPdelta-deficient mice. EMBO J 19, 27752785.
  • 40
    Dunah AW, Hueske E, Wyszynski M, Hoogenraad CC, Jaworski J, Pak DT, Simonetta A, Liu G & Sheng M (2005) LAR receptor protein tyrosine phosphatases in the development and maintenance of excitatory synapses. Nat Neurosci 8, 458467.
  • 41
    Dino MR, Harroch S, Hockfield S & Matthews RT (2006) Monoclonal antibody Cat-315 detects a glycoform of receptor protein tyrosine phosphatase beta/phosphacan early in CNS development that localizes to extrasynaptic sites prior to synapse formation. Neuroscience 142, 10551069.
  • 42
    Skarnes WC, Moss JE, Hurtley SM & Beddington RS (1995) Capturing genes encoding membrane and secreted proteins important for mouse development. Proc Natl Acad Sci USA 92, 65926596.
  • 43
    Schaapveld RQ, Schepens JT, Robinson GW, Attema J, Oerlemans FT, Fransen JA, Streuli M, Wieringa B, Hennighausen L & Hendriks WJ (1997) Impaired mammary gland development and function in mice lacking LAR receptor-like tyrosine phosphatase activity. Dev Biol 188, 134146.
  • 44
    Chagnon MJ, Uetani N & Tremblay ML (2004) Functional significance of the LAR receptor protein tyrosine phosphatase family in development and diseases. Biochem Cell Biol 82, 664675.
  • 45
    Yeo TT, Yang T, Massa SM, Zhang JS, Honkaniemi J, Butcher LL & Longo FM (1997) Deficient LAR expression decreases basal forebrain cholinergic neuronal size and hippocampal cholinergic innervation. J Neurosci Res 47, 348360.
  • 46
    Shultz LD, Schweitzer PA, Rajan TV, Yi T, Ihle JN, Matthews RJ, Thomas ML & Beier DR (1993) Mutations at the murine motheaten locus are within the hematopoietic cell protein-tyrosine phosphatase (Hcph) gene. Cell 73, 14451454.
  • 47
    Tsui FW, Martin A, Wang J & Tsui HW (2006) Investigations into the regulation and function of the SH2 domain-containing protein-tyrosine phosphatase, SHP-1. Immunol Res 35, 127136.
  • 48
    Tsui HW, Siminovitch KA, de Souza L & Tsui FW (1993) Motheaten and viable motheaten mice have mutations in the haematopoietic cell phosphatase gene. Nat Genet 4, 124129.
  • 49
    Arrandale JM, Gore-Willse A, Rocks S, Ren JM, Zhu J, Davis A, Livingston JN & Rabin DU (1996) Insulin signaling in mice expressing reduced levels of Syp. J Biol Chem 271, 2135321358.
  • 50
    Saxton TM, Henkemeyer M, Gasca S, Shen R, Rossi DJ, Shalaby F, Feng GS & Pawson T (1997) Abnormal mesoderm patterning in mouse embryos mutant for the SH2 tyrosine phosphatase Shp-2. EMBO J 16, 23522364.
  • 51
    Yang W, Klaman LD, Chen B, Araki T, Harada H, Thomas SM, George EL & Neel BG (2006) An Shp2/SFK/Ras/Erk signaling pathway controls trophoblast stem cell survival. Dev Cell 10, 317327.
  • 52
    Neel BG, Gu H & Pao L (2003) The ‘Shp’ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem Sci 28, 284293.
  • 53
    Dong XP, Li XM, Gao TM, Zhang EE, Feng GS, Xiong WC & Mei L (2006) Shp2 is dispensable in the formation and maintenance of the neuromuscular junction. Neurosignals 15, 5363.
  • 54
    Pao LI, Lam KP, Henderson JM, Kutok JL, Alimzhanov M, Nitschke L, Thomas ML, Neel BG & Rajewsky K (2007) B cell-specific deletion of protein-tyrosine phosphatase Shp1 promotes B-1a cell development and causes systemic autoimmunity. Immunity 27, 3548.
  • 55
    Ke Y, Lesperance J, Zhang EE, Bard-Chapeau EA, Oshima RG, Muller WJ & Feng GS (2006) Conditional deletion of Shp2 in the mammary gland leads to impaired lobulo-alveolar outgrowth and attenuated Stat5 activation. J Biol Chem 281, 3437434380.
  • 56
    Zhang SQ, Yang W, Kontaridis MI, Bivona TG, Wen G, Araki T, Luo J, Thompson JA, Schraven BL, Philips MR et al. (2004) Shp2 regulates SRC family kinase activity and Ras/Erk activation by controlling Csk recruitment. Mol Cell 13, 341355.
  • 57
    Glaser S, Anastassiadis K & Stewart AF (2005) Current issues in mouse genome engineering. Nat Genet 37, 11871193.
  • 58
    Salmond RJ, Huyer G, Kotsoni A, Clements L & Alexander DR (2005) The src homology 2 domain-containing tyrosine phosphatase 2 regulates primary T-dependent immune responses and Th cell differentiation. J Immunol 175, 64986508.
  • 59
    Mohi MG & Neel BG (2007) The role of Shp2 (PTPN11) in cancer. Curr Opin Genet Dev 17, 2330.
  • 60
    Gelb BD & Tartaglia M (2006) Noonan syndrome and related disorders: dysregulated RAS-mitogen activated protein kinase signal transduction. Hum Mol Genet 15(Spec No 2), R220R226.
  • 61
    Edouard T, Montagner A, Dance M, Conte F, Yart A, Parfait B, Tauber M, Salles JP & Raynal P (2007) How do Shp2 mutations that oppositely influence its biochemical activity result in syndromes with overlapping symptoms? Cell Mol Life Sci 64, 15851590.
  • 62
    Tonks NK (2006) Protein tyrosine phosphatases: from genes, to function, to disease. Nat Rev Mol Cell Biol 7, 833846.
  • 63
    Oganesian A, Poot M, Daum G, Coats SA, Wright MB, Seifert RA & Bowen-Pope DF (2003) Protein tyrosine phosphatase RQ is a phosphatidylinositol phosphatase that can regulate cell survival and proliferation. Proc Natl Acad Sci USA 100, 75637568.
  • 64
    Wang Z, Shen D, Parsons DW, Bardelli A, Sager J, Szabo S, Ptak J, Silliman N, Peters BA, van der Heijden MS et al. (2004) Mutational analysis of the tyrosine phosphatome in colorectal cancers. Science 304, 11641166.
  • 65
    Lee JW, Jeong EG, Lee SH, Nam SW, Kim SH, Lee JY & Yoo NJ (2007) Mutational analysis of PTPRT phosphatase domains in common human cancers. Apmis 115, 4751.
  • 66
    Stallings RL, Nair P, Maris JM, Catchpoole D, McDermott M, O’Meara A & Breatnach F (2006) High-resolution analysis of chromosomal breakpoints and genomic instability identifies PTPRD as a candidate tumor suppressor gene in neuroblastoma. Cancer Res 66, 36733680.
  • 67
    Purdie KJ, Lambert SR, Teh MT, Chaplin T, Molloy G, Raghavan M, Kelsell DP, Leigh IM, Harwood CA, Proby CM et al. (2007) Allelic imbalances and microdeletions affecting the PTPRD gene in cutaneous squamous cell carcinomas detected using single nucleotide polymorphism microarray analysis. Genes Chromosomes Cancer 46, 661669.
  • 68
    Zhao X, Weir BA, LaFramboise T, Lin M, Beroukhim R, Garraway L, Beheshti J, Lee JC, Naoki K, Richards WG et al. (2005) Homozygous deletions and chromosome amplifications in human lung carcinomas revealed by single nucleotide polymorphism array analysis. Cancer Res 65, 55615570.
  • 69
    Dube N, Bourdeau A, Heinonen KM, Cheng A, Loy AL & Tremblay ML (2005) Genetic ablation of protein tyrosine phosphatase 1B accelerates lymphomagenesis of p53-null mice through the regulation of B-cell development. Cancer Res 65, 1008810095.
  • 70
    Julien SG, Dube N, Read M, Penney J, Paquet M, Han Y, Kennedy BP, Muller WJ & Tremblay ML (2007) Protein tyrosine phosphatase 1B deficiency or inhibition delays ErbB2-induced mammary tumorigenesis and protects from lung metastasis. Nat Genet 39, 338346.
  • 71
    Bentires-Alj M & Neel BG (2007) Protein-tyrosine phosphatase 1B is required for HER2/Neu-induced breast cancer. Cancer Res 67, 24202424.
  • 72
    Tonks NK & Muthuswamy SK (2007) A brake becomes an accelerator: PTP1B – a new therapeutic target for breast cancer. Cancer Cell 11, 214216.
  • 73
    Elson A (1999) Protein tyrosine phosphatase epsilon increases the risk of mammary hyperplasia and mammary tumors in transgenic mice. Oncogene 18, 75357542.
  • 74
    Gil-Henn H & Elson A (2003) Tyrosine phosphatase-epsilon activates Src and supports the transformed phenotype of Neu-induced mammary tumor cells. J Biol Chem 278, 1557915586.
  • 75
    Berman-Golan D & Elson A (2007) Neu-mediated phosphorylation of protein tyrosine phosphatase epsilon is critical for activation of Src in mammary tumor cells. Oncogene 26, 70287037.
  • 76
    Östman A, Hellberg C & Böhmer FD (2006) Protein-tyrosine phosphatases and cancer. Nat Rev Cancer 6, 307320.
  • 77
    Mustelin T, Vang T & Bottini N (2005) Protein tyrosine phosphatases and the immune response. Nat Rev Immunol 5, 4357.
  • 78
    Dolton GM, Sathish JG & Matthews RJ (2006) Protein tyrosine phosphatases as negative regulators of the immune response. Biochem Soc Trans 34, 10411045.
  • 79
    Pao LI, Badour K, Siminovitch KA & Neel BG (2007) Nonreceptor protein-tyrosine phosphatases in immune cell signaling. Annu Rev Immunol 25, 473523.
  • 80
    Majeti R, Xu Z, Parslow TG, Olson JL, Daikh DI, Killeen N & Weiss A (2000) An inactivating point mutation in the inhibitory wedge of CD45 causes lymphoproliferation and autoimmunity. Cell 103, 10591070.
  • 81
    Hasegawa K, Martin F, Huang G, Tumas D, Diehl L & Chan AC (2004) PEST domain-enriched tyrosine phosphatase (PEP) regulation of effector/memory T cells. Science 303, 685689.
  • 82
    Vang T, Miletic AV, Bottini N & Mustelin T (2007) Protein tyrosine phosphatase PTPN22 in human autoimmunity. Autoimmunity 40, 453461.
  • 83
    Wise CA, Gillum JD, Seidman CE, Lindor NM, Veile R, Bashiardes S & Lovett M (2002) Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder. Hum Mol Genet 11, 961969.
  • 84
    Persson C, Savenhed C, Bourdeau A, Tremblay ML, Markova B, Bohmer FD, Haj FG, Neel BG, Elson A, Heldin CH et al. (2004) Site-selective regulation of platelet-derived growth factor beta receptor tyrosine phosphorylation by T-cell protein tyrosine phosphatase. Mol Cell Biol 24, 21902201.
  • 85
    Moffat J & Sabatini DM (2006) Building mammalian signalling pathways with RNAi screens. Nat Rev Mol Cell Biol 7, 177187.
  • 86
    Majeti R, Bilwes AM, Noel JP, Hunter T & Weiss A (1998) Dimerization-induced inhibition of receptor protein tyrosine phosphatase function through an inhibitory wedge. Science 279, 8891.
  • 87
    Bilwes AM, den Hertog J, Hunter T & Noel JP (1996) Structural basis for inhibition of receptor protein-tyrosine phosphatase-alpha by dimerization. Nature 382, 555559.
  • 88
    Xie Y, Massa SM, Ensslen-Craig SE, Major DL, Yang T, Tisi MA, Derevyanny VD, Runge WO, Mehta BP, Moore LA et al. (2006) Protein-tyrosine phosphatase (PTP) wedge domain peptides: a novel approach for inhibition of PTP function and augmentation of protein-tyrosine kinase function. J Biol Chem 281, 1648216492.
  • 89
    Chin CN, Sachs JN & Engelman DM (2005) Transmembrane homodimerization of receptor-like protein tyrosine phosphatases. FEBS Lett 579, 38553858.
  • 90
    Gross S, Blanchetot C, Schepens J, Albet S, Lammers R, den Hertog J & Hendriks W (2002) Multimerization of the protein-tyrosine phosphatase (PTP)-like insulin-dependent diabetes mellitus autoantigens IA-2 and IA-2beta with receptor PTPs (RPTPs). Inhibition of RPTPalpha enzymatic activity. J Biol Chem 277, 4813948145.
  • 91
    Yin H, Slusky JS, Berger BW, Walters RS, Vilaire G, Litvinov RI, Lear JD, Caputo GA, Bennett JS & DeGrado WF (2007) Computational design of peptides that target transmembrane helices. Science 315, 181718122.
  • 92
    Lee S, Faux C, Nixon J, Alete D, Chilton J, Hawadle M & Stoker AW (2007) Dimerization of protein tyrosine phosphatase sigma governs both ligand binding and isoform specificity. Mol Cell Biol 27, 17951808.
  • 93
    Yang T, Yin W, Derevyanny VD, Moore LA & Longo FM (2005) Identification of an ectodomain within the LAR protein tyrosine phosphatase receptor that binds homophilically and activates signalling pathways promoting neurite outgrowth. Eur J Neurosci 22, 21592170.
  • 94
    Paul S, Olausson P, Venkitaramani DV, Ruchkina I, Moran TD, Tronson N, Mills E, Hakim S, Salter MW, Taylor JR et al. (2007) The striatal-enriched protein tyrosine phosphatase gates long-term potentiation and fear memory in the lateral amygdala. Biol Psychiatry 61, 10491061.
  • 95
    Rashid-Doubell F, McKinnell I, Aricescu AR, Sajnani G & Stoker A (2002) Chick PTPsigma regulates the targeting of retinal axons within the optic tectum. J Neurosci 22, 50245033.
  • 96
    Bourdeau A, Dube N & Tremblay ML (2005) Cytoplasmic protein tyrosine phosphatases, regulation and function: the roles of PTP1B and TC-PTP. Curr Opin Cell Biol 17, 203209.
  • 97
    Bauler TJ, Hughes ED, Arimura Y, Mustelin T, Saunders TL & King PD (2007) Normal TCR signal transduction in mice that lack catalytically active PTPN3 protein tyrosine phosphatase. J Immunol 178, 36803687.
  • 98
    Pilecka I, Patrignani C, Pescini R, Curchod M-L, Perrin D, Xue Y, Yasenchak J, Clark A, Magnone M, Zaratin P et al. (2007) Protein tyrosine phosphatase H1 (PTP-H1/PTPN3) controls growth hormone receptor signaling and systemic growth. J Biol Chem 282, 3540535415.
  • 99
    Kina S, Tezuka T, Kusakawa S, Kishimoto Y, Kakizawa S, Hashimoto K, Ohsugi M, Kiyama Y, Horai R, Sudo K et al. (2007) Involvement of protein-tyrosine phosphatase PTPMEG in motor learning and cerebellar long-term depression. Eur J Neurosci 26, 22692278.
  • 100
    Braithwaite SP, Paul S, Nairn AC & Lombroso PJ (2006) Synaptic plasticity: one STEP at a time. Trends Neurosci 29, 452458.
  • 101
    Choi YS, Lin SL, Lee B, Kurup P, Cho HY, Naegele JR, Lombroso PJ & Obrietan K (2007) Status epilepticus-induced somatostatinergic hilar interneuron degeneration is regulated by striatal enriched protein tyrosine phosphatase. J Neurosci 27, 29993009.
  • 102
    Umeda S, Beamer WG, Takagi K, Naito M, Hayashi S, Yonemitsu H, Yi T & Shultz LD (1999) Deficiency of SHP-1 protein-tyrosine phosphatase activity results in heightened osteoclast function and decreased bone density. Am J Pathol 155, 223233.
  • 103
    Wu C, Sun M, Liu L & Zhou GW (2003) The function of the protein tyrosine phosphatase SHP-1 in cancer. Gene 306, 112.
  • 104
    Gronda M, Arab S, Iafrate B, Suzuki H & Zanke BW (2001) Hematopoietic protein tyrosine phosphatase suppresses extracellular stimulus-regulated kinase activation. Mol Cell Biol 21, 68516858.
  • 105
    Wang Y, Vachon E, Zhang J, Cherepanov V, Kruger J, Li J, Saito K, Shannon P, Bottini N, Huynh H et al. (2005) Tyrosine phosphatase MEG2 modulates murine development and platelet and lymphocyte activation through secretory vesicle function. J Exp Med 202, 15871597.
  • 106
    Araki T, Mohi MG, Ismat FA, Bronson RT, Williams IR, Kutok JL, Yang W, Pao LI, Gilliland DG, Epstein JA et al. (2004) Mouse model of Noonan syndrome reveals cell type- and gene dosage-dependent effects of Ptpn11 mutation. Nat Med 10, 849857.
  • 107
    Sarkozy A, Obregon MG, Conti E, Esposito G, Mingarelli R, Pizzuti A & Dallapiccola B (2004) A novel PTPN11 gene mutation bridges Noonan syndrome, multiple lentigines/LEOPARD syndrome and Noonan-like/multiple giant cell lesion syndrome. Eur J Hum Genet 12, 10691072.
  • 108
    Sirois J, Cote JF, Charest A, Uetani N, Bourdeau A, Duncan SA, Daniels E & Tremblay ML (2006) Essential function of PTP-PEST during mouse embryonic vascularization, mesenchyme formation, neurogenesis and early liver development. Mech Dev 123, 869880.
  • 109
    Nakahira M, Tanaka T, Robson BE, Mizgerd JP & Grusby MJ (2007) Regulation of signal transducer and activator of transcription signaling by the tyrosine phosphatase PTP-BL. Immunity 26, 163176.
  • 110
    Wansink DG, Peters W, Schaafsma I, Sutmuller RP, Oerlemans F, Adema GJ, Wieringa B, van der Zee CE & Hendriks W (2004) Mild impairment of motor nerve repair in mice lacking PTP-BL tyrosine phosphatase activity. Physiol Genom 19, 5060.
  • 111
    Nedachi T & Conti M (2004) Potential role of protein tyrosine phosphatase nonreceptor type 13 in the control of oocyte meiotic maturation. Development 131, 49874998.
  • 112
    Ogata M, Takada T, Mori Y, Uchida Y, Miki T, Okuyama A, Kosugi A, Sawada M, Oh-hora M & Hamaoka T (1999) Regulation of phosphorylation level and distribution of PTP36, a putative protein tyrosine phosphatase, by cell-substrate adhesion. J Biol Chem 274, 2071720724.
  • 113
    Gensler M, Buschbeck M & Ullrich A (2004) Negative regulation of HER2 signaling by the PEST-type protein-tyrosine phosphatase BDP1. J Biol Chem 279, 1211012116.
  • 114
    Fodero-Tavoletti MT, Hardy MP, Cornell B, Katsis F, Sadek CM, Mitchell CA, Kemp BE & Tiganis T (2005) Protein tyrosine phosphatase hPTPN20a is targeted to sites of actin polymerization. Biochem J 389, 343354.
  • 115
    Jui HY, Tseng RJ, Wen X, Fang HI, Huang LM, Chen KY, Kung HJ, Ann DK & Shih HM (2000) Protein-tyrosine phosphatase D1, a potential regulator and effector for Tec family kinases. J Biol Chem 275, 4112441132.
  • 116
    Toyooka S, Ouchida M, Jitsumori Y, Tsukuda K, Sakai A, Nakamura A, Shimizu N & Shimizu K (2000) HD-PTP: a novel protein tyrosine phosphatase gene on human chromosome 3p21.3. Biochem Biophys Res Commun 278, 671678.
  • 117
    Castiglioni S, Maier JA & Mariotti M (2007) The tyrosine phosphatase HD-PTP: a novel player in endothelial migration. Biochem Biophys Res Commun 364, 534539.
  • 118
    Skelton MR, Ponniah S, Wang DZ, Doetschman T, Vorhees CV & Pallen CJ (2003) Protein tyrosine phosphatase alpha (PTP alpha) knockout mice show deficits in Morris water maze learning, decreased locomotor activity, and decreases in anxiety. Brain Res 984, 110.
  • 119
    Bodrikov V, Leshchyns’ka I, Sytnyk V, Overvoorde J, den Hertog J & Schachner M (2005) RPTPalpha is essential for NCAM-mediated p59fyn activation and neurite elongation. J Cell Biol 168, 127139.
  • 120
    Su J, Muranjan M & Sap J (1999) Receptor protein tyrosine phosphatase alpha activates Src-family kinases and controls integrin-mediated responses in fibroblasts. Curr Biol 9, 505511.
  • 121
    Dominguez MG, Hughes VC, Pan L, Simmons M, Daly C, Anderson K, Noguera-Troise I, Murphy AJ, Valenzuela DM, Davis S et al. (2007) Vascular endothelial tyrosine phosphatase (VE-PTP)-null mice undergo vasculogenesis but die embryonically because of defects in angiogenesis. Proc Natl Acad Sci USA 104, 32433248.
  • 122
    Baumer S, Keller L, Holtmann A, Funke R, August B, Gamp A, Wolburg H, Wolburg-Buchholz K, Deutsch U & Vestweber D (2006) Vascular endothelial cell-specific phosphotyrosine phosphatase (VE-PTP) activity is required for blood vessel development. Blood 107, 47544762.
  • 123
    Alexander DR (2000) The CD45 tyrosine phosphatase: a positive and negative regulator of immune cell function. Semin Immunol 12, 349359.
  • 124
    Nakahara J, Seiwa C, Tan-Takeuchi K, Gotoh M, Kishihara K, Ogawa M, Asou H & Aiso S (2005) Involvement of CD45 in central nervous system myelination. Neurosci Lett 379, 116121.
  • 125
    Chiusaroli R, Knobler H, Luxenburg C, Sanjay A, Granot-Attas S, Tiran Z, Miyazaki T, Harmelin A, Baron R & Elson A (2004) Tyrosine phosphatase epsilon is a positive regulator of osteoclast function in vitro and in vivo. Mol Biol Cell 15, 234244.
  • 126
    Sully V, Pownall S, Vincan E, Bassal S, Borowski AH, Hart PH, Rockman SP & Phillips WA (2001) Functional abnormalities in protein tyrosine phosphatase epsilon-deficient macrophages. Biochem Biophys Res Commun 286, 184188.
  • 127
    Kolkman MJ, Streijger F, Linkels M, Bloemen M, Heeren DJ, Hendriks WJ & Van der Zee CE (2004) Mice lacking leukocyte common antigen-related (LAR) protein tyrosine phosphatase domains demonstrate spatial learning impairment in the two-trial water maze and hyperactivity in multiple behavioural tests. Behav Brain Res 154, 171182.
  • 128
    Bernabeu R, Yang T, Xie Y, Mehta B, Ma SY & Longo FM (2006) Downregulation of the LAR protein tyrosine phosphatase receptor is associated with increased dentate gyrus neurogenesis and an increased number of granule cell layer neurons. Mol Cell Neurosci 31, 723738.
  • 129
    Niu XL, Li J, Hakim ZS, Rojas M, Runge MS & Madamanchi NR (2007) Lar deficiency enhances IGF-1 signaling in vascular smooth muscle cells and promotes neointima formation in response to vascular injury. J Biol Chem 282, 1980819819.
  • 130
    Panagopoulos I, Pandis N, Thelin S, Petersson C, Mertens F, Borg A, Kristoffersson U, Mitelman F & Aman P (1996) The FHIT and PTPRG genes are deleted in benign proliferative breast disease associated with familial breast cancer and cytogenetic rearrangements of chromosome band 3p14. Cancer Res 56, 48714875.
  • 131
    van Doorn R, Zoutman WH, Dijkman R, de Menezes RX, Commandeur S, Mulder AA, van der Velden PA, Vermeer MH, Willemze R, Yan PS et al. (2005) Epigenetic profiling of cutaneous T-cell lymphoma: promoter hypermethylation of multiple tumor suppressor genes including BCL7a, PTPRG, and p73. J Clin Oncol 23, 38863896.
  • 132
    Noguchi T, Tsuda M, Takeda H, Takada T, Inagaki K, Yamao T, Fukunaga K, Matozaki T & Kasuga M (2001) Inhibition of cell growth and spreading by stomach cancer-associated protein-tyrosine phosphatase-1 (SAP-1) through dephosphorylation of p130cas. J Biol Chem 276, 1521615224.
  • 133
    Kose H, Sakai T, Tsukumo S, Wei K, Yamada T, Yasutomo K & Matsumoto K (2007) Maturational arrest of thymocyte development is caused by a deletion in the receptor-like protein tyrosine phosphatase kappa gene in LEC rats. Genomics 89, 673677.
  • 134
    Nakamura M, Kishi M, Sakaki T, Hashimoto H, Nakase H, Shimada K, Ishida E & Konishi N (2003) Novel tumor suppressor loci on 6q22-23 in primary central nervous system lymphomas. Cancer Res 63, 737741.
  • 135
    Koop EA, Gebbink MF, Sweeney TE, Mathy MJ, Heijnen HF, Spaan JA, Voest EE, VanBavel E & Peters SL (2005) Impaired flow-induced dilation in mesenteric resistance arteries from receptor protein tyrosine phosphatase-mu-deficient mice. Am J Physiol Heart Circ Physiol 288, H1218H1223.
  • 136
    Koop EA, Lopes SM, Feiken E, Bluyssen HA, van der Valk M, Voest EE, Mummery CL, Moolenaar WH & Gebbink MF (2003) Receptor protein tyrosine phosphatase mu expression as a marker for endothelial cell heterogeneity; analysis of RPTPmu gene expression using LacZ knock-in mice. Int J Dev Biol 47, 345354.
  • 137
    Wharram BL, Goyal M, Gillespie PJ, Wiggins JE, Kershaw DB, Holzman LB, Dysko RC, Saunders TL, Samuelson LC & Wiggins RC (2000) Altered podocyte structure in GLEPP1 (Ptpro)-deficient mice associated with hypertension and low glomerular filtration rate. J Clin Invest 106, 12811290.
  • 138
    Motiwala T, Majumder S, Kutay H, Smith DS, Neuberg DS, Lucas DM, Byrd JC, Grever M & Jacob ST (2007) Methylation and silencing of protein tyrosine phosphatase receptor type O in chronic lymphocytic leukemia. Clin Cancer Res 13, 31743181.
  • 139
    Goodyear RJ, Legan PK, Wright MB, Marcotti W, Oganesian A, Coats SA, Booth CJ, Kros CJ, Seifert RA, Bowen-Pope DF et al. (2003) A receptor-like inositol lipid phosphatase is required for the maturation of developing cochlear hair bundles. J Neurosci 23, 92089219.
  • 140
    Chirivi RG, Noordman YE, Van der Zee CE & Hendriks WJ (2007) Altered MAP kinase phosphorylation and impaired motor coordination in PTPRR deficient mice. J Neurochem 101, 829840.
  • 141
    Sapieha PS, Duplan L, Uetani N, Joly S, Tremblay ML, Kennedy TE & Di Polo A (2005) Receptor protein tyrosine phosphatase sigma inhibits axon regrowth in the adult injured CNS. Mol Cell Neurosci 28, 625635.
  • 142
    Batt J, Asa S, Fladd C & Rotin D (2002) Pituitary, pancreatic and gut neuroendocrine defects in protein tyrosine phosphatase-sigma-deficient mice. Mol Endocrinol 16, 155169.
  • 143
    Elchebly M, Wagner J, Kennedy TE, Lanctot C, Michaliszyn E, Itie A, Drouin J & Tremblay ML (1999) Neuroendocrine dysplasia in mice lacking protein tyrosine phosphatase sigma. Nat Genet 21, 330333.
  • 144
    McLean J, Batt J, Doering LC, Rotin D & Bain JR (2002) Enhanced rate of nerve regeneration and directional errors after sciatic nerve injury in receptor protein tyrosine phosphatase sigma knock-out mice. J Neurosci 22, 54815491.
  • 145
    Meathrel K, Adamek T, Batt J, Rotin D & Doering LC (2002) Protein tyrosine phosphatase sigma-deficient mice show aberrant cytoarchitecture and structural abnormalities in the central nervous system. J Neurosci Res 70, 2435.
  • 146
    Thompson KM, Uetani N, Manitt C, Elchebly M, Tremblay ML & Kennedy TE (2003) Receptor protein tyrosine phosphatase sigma inhibits axonal regeneration and the rate of axon extension. Mol Cell Neurosci 23, 681692.
  • 147
    Chagnon MJ, Elchebly M, Uetani N, Dombrowski L, Cheng A, Mooney RA, Marette A & Tremblay ML (2006) Altered glucose homeostasis in mice lacking the receptor protein tyrosine phosphatase sigma. Can J Physiol Pharmacol 84, 755763.
  • 148
    Muise AM, Walters T, Wine E, Griffiths AM, Turner D, Duerr RH, Regueiro MD, Ngan BY, Xu W, Sherman PM et al. (2007) Protein-tyrosine phosphatase sigma is associated with ulcerative colitis. Curr Biol 17, 12121218.
  • 149
    Zhang X, Guo A, Yu J, Possemato A, Chen Y, Zheng W, Polakiewicz RD, Kinzler KW, Vogelstein B, Velculescu VE et al. (2007) Identification of STAT3 as a substrate of receptor protein tyrosine phosphatase T. Proc Natl Acad Sci USA 104, 40604064.
  • 150
    Besco JA, Hooft van Huijsduijnen R, Frostholm A & Rotter A (2006) Intracellular substrates of brain-enriched receptor protein tyrosine phosphatase rho (RPTPrho/PTPRT). Brain Res 1116, 5057.
  • 151
    Yan HX, Yang W, Zhang R, Chen L, Tang L, Zhai B, Liu SQ, Cao HF, Man XB, Wu HP et al. (2006) Protein-tyrosine phosphatase PCP-2 inhibits beta-catenin signaling and increases E-cadherin-dependent cell adhesion. J Biol Chem 281, 1542315433.
  • 152
    Doumont G, Martoriati A, Beekman C, Bogaerts S, Mee PJ, Bureau F, Colombo E, Alcalay M, Bellefroid E, Marchesi F et al. (2005) G1 checkpoint failure and increased tumor susceptibility in mice lacking the novel p53 target Ptprv. EMBO J 24, 30933103.
  • 153
    Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, Dacquin R, Mee PJ, McKee MD, Jung DY et al. (2007) Endocrine regulation of energy metabolism by the skeleton. Cell 130, 456469.
  • 154
    Doumont G, Martoriati A & Marine JC (2005) PTPRV is a key mediator of p53-induced cell cycle exit. Cell Cycle 4, 17031705.
  • 155
    Fujikawa A, Shirasaka D, Yamamoto S, Ota H, Yahiro K, Fukada M, Shintani T, Wada A, Aoyama N, Hirayama T et al. (2003) Mice deficient in protein tyrosine phosphatase receptor type Z are resistant to gastric ulcer induction by VacA of Helicobacter pylori. Nat Genet 33, 375381.
  • 156
    Harroch S, Furtado GC, Brueck W, Rosenbluth J, Lafaille J, Chao M, Buxbaum JD & Schlessinger J (2002) A critical role for the protein tyrosine phosphatase receptor type Z in functional recovery from demyelinating lesions. Nat Genet 32, 411414.