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K. S. Erdmann, Department of Cell Biology, Yale University School of Medicine, New Haven, CT, USA. Fax: + 1 203 737 1762, Tel.: + 1 203 737 4473, E-mail: firstname.lastname@example.org
The protein tyrosine phosphatase PTP-Basophil (PTP-Bas) and its mouse homologue, PTP-Basophil-like (PTP-BL), are high molecular mass protein phosphatases consisting of a number of diverse protein–protein interaction modules. Several splicing variants of these phosphatases are known to exist thus demonstrating the complexity of these molecules. PTP-Bas/BL serves as a central scaffolding protein facilitating the assembly of a multiplicity of different proteins mainly via five different PDZ domains. Many of these interacting proteins are implicated in the regulation of the actin cytoskeleton. However, some proteins demonstrate a nuclear function of this protein tyrosine phosphatase. PTP-Bas is involved in the regulation of cell surface expression of the cell death receptor, Fas. Moreover, it is a negative regulator of ephrinB phosphorylation, a receptor playing an important role during development. The phosphorylation status of other proteins such as RIL, IκBα and β-catenin can also be regulated by this phosphatase. Finally, PTP-BL has been shown to be involved in the regulation of cytokinesis, the last step in cell division. Although the precise molecular function of PTP-Bas/BL is still elusive, current data suggest clearly that PTP-Bas/BL belongs to the family of PDZ domain containing proteins involved in the regulation of the cytoskeleton and of intracellular vesicular transport processes.
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Protein phosphorylation is one of the most prominent post-translational modifications regulating the activity, interaction capability and subcellular localization of proteins. In particular, protein tyrosine phosphorylation has been identified as a major regulator of signal transduction in higher eukaryotes. Protein target phosphorylation is catalysed by protein tyrosine kinases and counteracted by the activity of protein tyrosine phosphatases .
The family of protein tyrosine phosphatases (PTPs) is divided into two major subtypes: (a) the receptor-like and (b) the nonreceptor subtype. The receptor-like subtype contains one transmembrane domain and one or two phosphatase domains at the C-terminus, which faces the cytosol. The nonreceptor subtype is characterized by the lack of a transmembrane domain and is a cytosolic or membrane-associated phosphatase .
The nonreceptor protein tyrosine phosphatases PTP-Bas/BL [3,4], PTPH1/PTP-MEG [5,6] and PTPD1/PTP-RL10 [7,8] belong to a protein tyrosine phosphatase family characterized by the presence of a Four point one/Ezrin/Radixin/Moesin (FERM) domain (FERM-PTP family). PTPD1 has been implicated in vesicular trafficking processes due to its interaction with a kinesin motor protein  and in the regulation of the Tec tyrosine kinase family . PTPH1, has been suggested to play a role in vesicular fusion processes of the endoplasmatic reticulum , in cell cycle regulation  and in the regulation of the tumor necrosis factor α-convertase (TACE) . This review will focus on current knowledge of the largest member of this FERM-PTP family, the protein tyrosine phosphatase Basophil/Basophil-like.
The modular structure of the protein tyrosine phosphatase-Basophil/Basophil-like
The human homologue of this protein tyrosine phosphatase was discovered by employing a PCR-based strategy to identify new protein tyrosine phosphatases using conserved regions within the catalytic domain. Originally, it was cloned from a basophil cell line, consequently, the new protein tyrosine phosphatase was named PTP-Basophil (PTP-Bas) . Using a similar strategy, it was cloned in parallel from a human glioma cell line and a human breast carcinoma cell line and named PTPL1 and hPTP1e, respectively [14,15]. Finally, due to its interaction with the human cell surface receptor Fas, it was renamed as FAP-1 (Fas-associated phosphatase-1) . The mouse homologue was cloned by two independent approaches and called RIP and also PTP-BL − PTP-basophil-like − referring to its human homologue (PTP-Bas) [4,17]. To simplify reading and to avoid confusion within this review the human homologue will be consequently assigned PTP-Bas and the mouse homologue as PTP-BL.
The protein tyrosine phosphatase PTP-Bas/BL is a highly modular protein of about 2490 amino acids length (molecular mass ≈ 270 kDa) (Fig. 1). The extreme N-terminus contains a kinase noncatalytic C-lobe (KIND) domain, a protein module identified recently that shows homology to the regulatory C-lobe of protein kinases but that lacks catalytic activity . The function of this domain is currently unknown but a role in mediating protein–protein interactions has been suggested. The KIND domain is followed by a Four-point-one/Ezrin/Radixin/Moesin (FERM) domain. FERM domains are known to play an important role in connecting plasma membrane receptors to the cytoskeleton . Furthermore, PTP-Bas/BL comprises five different PSD-95/Drosophila discs large/Zonula occludens (PDZ) domains . PDZ domains are protein–protein interaction domains playing a fundamental role in the assembly of supramolecular protein complexes . Finally, the protein tyrosine phosphatase domain is located at the extreme C-terminus of the molecule.
The complexity of the PTP-Bas/BL molecule is further increased by alternative splicing that is observed in the N-terminus between the FERM domain and the first PDZ domain and within the second PDZ domain [3,4,14,16,22]. Additional minor alternative splice products have been described for PTP-Bas predicting C-terminal truncated versions of the PTP-Bas protein . Given the presence of at least seven protein–protein interaction domains including the KIND, FERM and five PDZ domains, PTP-Bas/BL functions most probably as a major scaffolding protein (see below).
Expression pattern of PTP-BL
RNA in situ hybridization experiments show that the expression pattern of PTP-BL is highly regulated during development . Early in development, PTP-BL is expressed ubiquitously throughout the embryo. At later stages, PTP-BL becomes restricted to epithelial and neuronal cell lineages, e.g. epithelia of the skin, oesophagus, stomach, nasal cavity, lung, kidney, ureter, and the bladder. Moreover, expression has been observed in the ependymal cell layer, an epithelial cell layer surrounding the ventricles of the brain . A similar expression pattern was observed in transgenic mice used to analyse the distribution of a truncated version of PTP-BL lacking the portion of the protein C-terminal to the first PDZ domain and fused to β-galactosidase . In this in vivo model, additional expression was detected in the pigmented epithelial layer of the eye, in the infundibulum and the anterior lobe of the pituitary. Most interestingly, a timely regulated expression could be observed in peripheral sensory and sympathetic neurons.
With regard to a possible role of PTP-BL under pathological conditions, it was demonstrated that the human homologue PTP-Bas is up regulated in a number of tumour cell lines [24–26]. Most strikingly, PTP-Bas is up regulated in many ovarian tumours . This is of particular interest, as PTP-Bas has been demonstrated to mediate resistance to Fas induced apoptosis (see below) . Given that apoptosis is one of the mechanisms to eliminate transformed cells in a multicellular organism to avoid the onset of cancer, a role of PTP-Bas/BL as a tumour suppressor is conceivable.
At subcellular levels, PTP-BL shows an apical localization in epithelial cells and is accumulated in axons and growth cones of sympathetic and sensory neurons [23,28,29]. Furthermore, PTP-Bas localizes to the Golgi apparatus and to the nucleus [22,30]. Recently, it has been shown that a specific splicing variant of PTP-BL accumulates at the centrosome and at the spindle midzone during cell division and is part of the midbody late in cytokinesis  (for details see below).
Domain specific interactions of PTP-Bas/BL
Knowledge about PTP-Bas/BL has increased due to the identification of a number of proteins interacting with one or two of the interaction domains present in PTP-Bas/BL. A summary of these domain specific interactions is given below (see also Fig. 2).
Recently, the KIND domain was identified by its similarity to the C-terminal protein kinase catalytic fold (C-lobe). However, the absence of catalytic and activation loops suggests that this domain is probably noncatalytic . The molecular function of this ≈ 200 amino acid new protein module is currently unknown but given that the C-lobe domain serves as a protein/protein interaction domain in protein kinases a similar role for the KIND domain is conceivable. Further experiments are needed to clarify the molecular function of the KIND domain in PTP-Bas/BL.
FERM domains play an important role at the interface between the plasma membrane and the cytoskeleton . These domains have a length of about 300 amino acids and can be divided into three subdomains (A–C) as revealed by X-ray analysis. FERM domains are known to bind to a number of cell surface receptors [19,32]. In addition, binding to 1-phosphatidylinositol 4,5-biphosphate [PtdIns(4,5)P2 or PIP2) has been demonstrated . Most recently, it has been reported that the FERM domain of PTP-Bas is also able to interact with PIP2 . This interaction has been suggested to be important for membrane localization of PTP-Bas. Moreover, the FERM domain of PTP-BL was described to target the protein to the apical membrane in cultured epithelial cells as well as in vivo[4,23]. Besides binding to PIP2, colocalization as well as cosedimentation with filamentous actin has been demonstrated suggesting an association with the actin cytoskeleton . However, there are currently no proteins known to interact directly with the FERM domain of PTP-Bas/BL.
PDZ domains are able to interact selectively with the C-termini of their target proteins [21,35,36]. However, there are also examples of PDZ domain binding to internal sequences [35,37]. Recently, it has been shown that PDZ domains are not only protein–protein interaction domains but can also serve as PIP (PtdInsP) binding modules . PDZ domains have a length of ≈ 90 amino acids and adopt an α/β-fold consisting of six β-sheets and two α-helices [39,40]. Currently, only the NMR-structure of one (PDZ2) of the five PDZ domains of PTP-Bas/BL is available [41,42]. Although the overall structure of the PDZ2 domain fits well into the common fold of PDZ domains, it shows an unusual foldback of the loop between β2 and β3 to the backbone. This loop has been implicated in the regulation of target recognition of the PDZ2 domain [22,43]. Indeed the NMR-structure of a splice variant of the PDZ2 domain (PDZ2b), with an extended β2/β3 loop, revealed that this foldback can even interfere with protein target binding .
There is an increasing number of proteins known to interact with one or more of the PDZ domains of PTP-BL/PTP-Bas.
An interaction of PDZ1 with the bromodomain-containing protein BP75 and with the transcription regulator IκBα was demonstrated [45,46]. Although the function of BP75 is unknown, bromodomains are thought to interact with acetylated lysine residues that are present in histone proteins, thus, hinting at a possible function of BP75 in the nucleus . This is in line with its nuclear localization and the capability of BP75 to translocate the PDZ1 domain of PTP-BL to the nucleus. Interaction of BP75 with PTP-BL needs an intact C-terminus of BP75 although the C-terminus alone is insufficient for binding.
Interaction of IκBα with PDZ1 is mediated via its ankyrin repeats. IκBα is an inhibitor of the transcription factor NFκB. A complex consisting of both proteins is formed in the cytosol preventing NFκB from entering the nucleus. There are two pathways involved in dissociation of this complex. In the first pathway, IκBα is phosphorylated on Ser32 and 36 resulting in its degradation by the ubiquitin proteasome system. In the second pathway, IκBα is phosphorylated on Tyr42 leading to dissociation without degradation [48,49]. Indeed, IκBα is a substrate for PTP-Bas phosphatase, shown by an increase in tyrosine phosphorylation of IκBα after transfection of a PTP-Bas version lacking phosphatase activity . Furthermore, a substrate trapping mutant of PTP-Bas was found to bind selectively tyrosine-phosphorylated IκBα. The interaction of IκBα with PTP-Bas provides evidence for a regulation of NFκB dependent transcription via PTP-Bas [46,51].
A number of interacting proteins were shown to interact with the PDZ2 domain of PTP-Bas/BL. The human cell surface protein Fas was the first protein reported to interact with the PDZ2 domain of PTP-Bas (FAP-1) . However, the corresponding mouse homologue of Fas does not bind to PTP-BL  (see below). The neurotrophin receptor p75NTR has also been suggested to interact with the PDZ2 domain of PTP-Bas . Additional proteins known to bind to the PDZ2 domain are the LIM domain containing proteins RIL and Trip6/ZRP-1 [37,53,54]. RIL is also able to interact with PDZ4 (see below). Little is known about the molecular functions of RIL and Trip6/ZRP-1 but a regulatory role for the actin cytoskeleton has been suggested for both of them. Recently, Trip6 has been shown to accumulate at focal adhesions and to interact with the adaptor protein p130Cas (Crk associated substrate) implicating this molecule in the regulation of cell adhesion . Another protein involved in cell adhesion regulation, the tumour suppressor protein APC (adenomatous polyposis coli protein), interacts selectively with the PDZ2 domain of PTP-BL . Interestingly, it has been demonstrated that APC interacts only with one of the two splice variants of PDZ2 (PDZ2a). The insertion of five amino acids within the β2/β3-loop present in PDZ2b led to a complete abolishment of the interaction with APC . APC is involved in many sporadic and inherited forms of colon carcinoma. One important role of APC is the regulation of the protein β-catenin. β-catenin is involved in cell adhesion processes via the transmembrane receptor cadherin and plays a role in the regulation of transcription via the transcription factor LEF/TCF (lymphocyte enhancer binding factor/T-cell factor) . APC also interacts with a recently identified rho exchange factor (Asef) and is involved in the regulation of the tubulin and actin cytoskeleton .
The only protein known to interact with the PDZ3 domain of PTP-BL is the protein kinase C-related kinase-2 (PRK2) . PRK2 is a cytosolic serine/threonine kinase regulated by the monomeric G-protein rho. PRK2 is implicated in the modulation of the actin cytoskeleton and based on its similarity to PRK1 a potential role in the regulation of intracellular vesicular trafficking has been proposed [59–61]. Interestingly, the interaction is mediated via an unusual PDZ domain binding motif at the C-terminus of PRK2 (DWC).
Proteins known to interact with the PDZ4 domain of PTP-Bas/PTP-BL are the LIM containing proteins RIL (also able to interact with PDZ2, see above) and CRIP2, the rhoGAP protein PARG as well as the class B transmembrane ephrin receptor (ephrinB) [37,62–64]. The PDZ4 domain shows the highest variability in its target binding motifs. RIL and CRIP2 bind via their LIM domains to the PDZ4 domain whereas ephrinB binds via a C-terminal PDZ domain II binding motif. However, PARG neither contains a LIM domain nor a PDZ domain II binding consensus sequence and the molecular mechanism of binding remains currently unclear.
Currently, there are no proteins known to interact with the PDZ5 domain although it was demonstrated that the PDZ5 domain of PTP-BL, like the PDZ2 and PDZ3 domains, is able to interact with PIP2 .
Substrates of the PTP-Bas/BL protein tyrosine phosphatase domain
Crucial for the understanding of PTP-Bas/BL function is the identification of specific substrates of the protein tyrosine phosphatase domain. Using recombinant glutathione-S-transferase fusionproteins of the ≈ 230 amino acids comprising phosphatase domain it has been demonstrated that PTP-Bas/BL is a bona fide tyrosine phosphatase [15,22]. Currently, several proteins are known to serve as substrate for the protein tyrosine phosphatase domain of PTP-Bas/BL. Theses proteins are RIL, IκBα and ephrinB, which have been shown to serve as substrates in vivo using transfected cell lines [29,37,46]. Moreover, as mentioned above, IκBα could be coprecipitated using a substrate trapping mutant of the PTP-Bas phosphatase domain . Finally, β-catenin and c-src could be dephosphroylated in vitro by PTP-BL phosphatase . However, the functional consequences of PTP-Bas/BL induced dephosphorylation have not been determined yet.
A potential function of PTP-Bas in Fas-mediated apoptosis
In spite of the large number of examples of protein interactions, a direct functional involvement of PTP-Bas/BL in specific pathways is limited. However, a number of reports have described a potential role of PTP-Bas in conferring resistance to Fas-induced cell death [26,65]. Fas is a type-I transmembrane receptor and a member of the tumor necrosis factor-receptor/nerve growth factor receptor-family [66,67]. The Fas receptor itself does not contain catalytic activity but is able to recruit a ‘death signalling complex’ after activation by the Fas-ligand . PTP-Bas binds via its PDZ2 domain to the extreme C-terminus of human Fas, which is known to exert a negative regulatory effect on Fas signalling [69,70]. Indeed, it was shown that Jurkat T leukemia cells, which do not express endogenous PTP-Bas, were rendered more resistant to Fas-induced apoptosis after overexpression of PTP-Bas . Further evidence for a role of PTP-Bas in regulating Fas signalling was established by injection experiments using a tripeptide derived from the extreme C-terminus of human Fas. Injection of this tripeptide into a colon cancer cell line or into thyrocytes restored sensitivity to Fas-induced cell death [71,72]. In addition, a correlation of PTP-Bas expression and sensitivity to Fas induced apoptosis has been observed in a number of different tumour cell lines [16,65,73]. It was also suggested that hepatomablastoma cells avoid apoptosis from coexpressing Fas and Fas-ligand by expressing PTP-BAS as a negative regulator of Fas signalling . An up regulation of PTP-BAS has been observed in ovarian cancers and ovarian cancer cell lines show a correlation of Fas-induced cell death resistance and PTP-BAS expression . PTP-Bas has also been implicated in the escape of HTLV1-infected T cells from Fas-mediated immune surveillance and finally, down regulation of PTP-Bas has been suggested to underlie the increased apoptotic death of hematopoitic cells in myelodysplastic syndrome [24,74]. However, the interaction between Fas and PTP-Bas is evolutionary not conserved, thus, mouse Fas does not interact with PTP-BL, the mouse homologue of PTP-Bas. Moreover, PTP-BL was not able to confer resistance or to decrease sensitivity to human Fas induced cell death, although PTP-BL is able to interact with human Fas via its PDZ2 and PDZ4 domain . There are also reports unable to identify any correlation between sensitivity to Fas-induced cell death and expression of PTP-Bas . Moreover, there is evidence that PTP-Bas can even exert a pro-apoptotic effect in human breast cancer cells, which is associated with an early inhibition of the insulin receptor substrate-1/PtdIns 3-kinase pathway .
The mechanism of how PTP-Bas is able to confer resistance to Fas-induced apoptosis, at least in some cell lines, is currently unclear, although regulation of tyrosine phosphorylation of Fas has been suggested . Recently however, two reports point to a possible role of PTP-BAS in the regulation of Fas cell surface expression.
PTP-Bas is able to regulate cell surface expression of Fas
As mentioned above, a number of cell lines are resistant to Fas-induced cell death. A similar observation has been made for several pancreatic adenocarcinoma cell lines . To elucidate a possible mechanism for PTP-Bas mediated resistance to Fas-induced apoptosis, Ungefroren et al. analysed the subcellular distribution of PTP-Bas and Fas in Panc89 cells upon stimulation with Fas-ligand . Unstimulated cells showed limited colocalization of PTP-Bas and Fas. However, upon treatment with Fas-ligand, colocalization of PTP-Bas and Fas was increased significantly. Strong colocalization was then observed at the Golgi apparatus and at peripheral vesicular structures. This increase in colocalization to intracellular compartments was accompanied by a strong decrease in Fas surface expression. However, this accumulation to intracellular stores was not observed in Capan-1 cells, a pancreatic adenocarcinoma cell line lacking PTP-Bas expression and being sensitive to Fas induced apoptosis. Based on the spatial temporal relationship of PTP-Bas and Fas the authors suggested an interfering role of PTP-Bas with the translocation of Fas from intracellular stores to the plasma membrane.
These results were recently confirmed and extended analysing the expression of PTP-Bas and Fas in melanoma cell lines . Several melanoma cell lines show a correlation between PTP-Bas expression and reduced cell surface expression of a transfected Fas-GFP fusion protein. Moreover, expression of PTP-Bas in a melanoma cell line lacking endogenous PTP-Bas (FEMX) redistributed Fas-GFP from the cell surface to intracellular pools. Similar results were obtained analysing the subcellular distribution of endogenous Fas. The inhibitory effect of PTP-Bas on cell surface expression of Fas was dependent on the presence of the PDZ2 and protein tyrosine phosphatase domain of PTP-Bas. Moreover, an intact C-terminus of Fas was crucial for the interfering role of PTP-Bas in Fas trafficking.
In summary, both reports provide strong evidence that PTP-Bas is able to act as a negative regulator of Fas cell surface expression giving an explanation for its inhibitory role in Fas-induced cell death. In principle, there are two major possibilities of how PTP-Bas could down regulate cell surface expression of Fas (Fig. 3A). Firstly, PTP-Bas could increase the trafficking of Fas from the cell surface to intracellular pools, disturbing the equilibrium of endocytotic and secretory events leading to a net decrease of Fas cell surface expression. Secondly, the recycling of Fas as well as the transport from intracellular stores to the cell surface could be affected. Both possibilities are not exclusive and given the modular complexity of PTP-Bas, an involvement in both processes has to be considered. Taken together, PTP-Bas joins the increasing number of PDZ-containing proteins involved in intracellular trafficking processes [78,79]. However, further experiments are needed to elucidate the precise function of PTP-Bas in receptor trafficking.
PTP-BL is a negative regulator of ephrinB phosphorylation – the switch model of ephrinB signalling
As described above, the ephrinB receptor interacts with the fourth PDZ domain of PTP–Bas. This interaction has been confirmed for mouse ephrinB and PTP-BL [29,64]. EphrinB is a type-I transmembrane receptor with no obvious catalytic activity in its cytoplasmic domain. However, ephrinB is part of a dual receptor system consisting of the ephrins and the erythropoetin-producing human hepatocellular derived (eph)-receptors. Eph-receptors belong to the large family of receptor tyrosine kinases.
The ephrin/eph-receptor system regulates an amazing variety of developmental processes, including cell migration, angiogenesis, segmentation and compartment boundary formation as well as synaptogenesis and axon guidance [80–82]. The ephrinB/eph-receptor system is able to induce a bi-directional signalling involving src kinase family-dependent tyrosine phosphorylation of conserved tyrosine residues at the cytoplasmic domain of ephrinB. Tyrosine–phosphorylated ephrinB then engages the SH2/SH3 adaptor molecule, GRB4, leading to further downstream signalling .
All ephrinB molecules contain a class II PDZ domain binding motif, –YXV, at their C-terminus . This motif has been shown to be crucial for the interaction with the fourth PDZ domain of PTP-Bas/BL (see above). PTP-BL is able to dephosphorylate ephrinB in vitro and overexpression of PTP-BL in HeLa cells stably transfected with ephrinB led to a significant decrease in ephrinB tyrosine phosphorylation. This interfering effect of PTP-BL on tyrosine phosphorylation of ephrinB was dependent on a catalytically active phosphatase domain . After stimulation with eph-receptor bodies, PTP-BL is recruited to ephrinB with delayed kinetics showing a tight correlation with the kinetics of ephrinB dephosphorylation. This led to the proposal of a switch model of ephrinB signalling (Fig. 3C) After binding to the cognate eph-receptor, ephrinB becomes phosphorylated at conserved tyrosine residues leading to the recruitment of SH2 domains containing proteins like GRB4. This is followed by binding to PTP-BL and subsequent dephosphorylation of ephrinB, switching off the phosphotyrosine dependent signalling and replacing it with a PDZ depending signalling .
PTP-Bas/PTP-BL is involved in the regulation of cytokinesis
Besides being involved in Fas trafficking and ephrinB signalling, a regulatory function of PTP-BL in cytokinesis has been suggested (Fig. 3B) . Cytokinesis is the last step of mitosis, dividing the cell into two parts after chromosome segregation. In mammalian cells, an actin–myosin ring is established beneath the plasma membrane accomplishing the division of the cytoplasm by contraction. The spindle midzone is formed in late anaphase by bundles of interdigitating microtubules and plays an important role in the regulation of cytokinesis . A detailed localization study of PTP-Bas in HeLa cells revealed that its localization is highly regulated during cell division. PTP-Bas accumulates at the spindle midzone during anaphase and becomes part of the midbody at the end of cytokinesis . Moreover, PTP-Bas is highly enriched at centrosomes. A domain specific localization analysis of the mouse homologue PTP-BL showed that PTP-BL is targeted to the midbody and to the centrosome by a specific splice variant of the N-terminus characterized by an insertion of 182 amino acids. Additionally, it was demonstrated that the FERM domain of PTP-BL is associated with the actin-based contractile ring and can be cosedimented with filamentous actin (F-actin), whereas the N-terminus can be cosedimented with microtubules. Elevating the expression level of wildtype PTP-BL or expression of PTP-BL with an inactive tyrosine phosphatase domain interfered with the contraction of the contractile ring. The defects in contractile ring contraction led to a significant increase of multinucleate cells suggesting a regulatory role of PTP-BL in cytokinesis. Currently, the precise function of PTP-BL in cytokinesis is not known, however, signal transduction via the small G-protein rho plays an important role in contractile ring assembly and in the regulation of its contraction during cytokinesis . PTP-Bas/BL has been shown to interact with the rho GTPase activating protein PARG and the rho regulated protein kinase, PRK2, implicating PTP-BL in a rho signaling pathway probably relevant to cytokinesis. In additon, PTP-BL is able to interact with F-actin and with microtubules, suggesting a role in connecting the contractile ring with the spindle midzone microtubules thereby coordinating cleavage furrow ingression with microtubule dynamics. Finally, given the role of PTP-Bas in trafficking of Fas (see above), PTP-BL could be important for targeted vesicle transport during cleavage furrow ingression, which has been demonstrated to be important for the final step of cytokinesis .
PTP-Bas/BL is an exceptionally large protein tyrosine phosphatase comprising a number of protein–protein interaction domains. As summarized above, many proteins have been identified as interacting with one or two of the five PDZ domains of PTP-Bas/BL. Moreover, PTP-BL is associated with F-actin and microtubules and binding to PIP2 has been demonstrated. Thus, PTP-BL/Bas serves clearly as a major scaffolding protein of a supramolecular protein complex. However, in spite of the large number of interacting proteins a clear cut function has not been assigned to PTP-Bas/BL. Given the modular complexity of PTP-Bas/BL and the number of different splicing variants it is reasonable to assume that this protein tyrosine phosphatase is involved in a number of different physiological processes. This is already reflected in the diversity of biological systems where an involvement of PTP-BL/PTP-Bas has already been defined (Fas trafficking, ephrinB signaling and regulation of cytokinesis). Moreover, there is evidence that PTP-Bas/BL is also part of a protein complex within the nucleus. A challenge for the future will be to elucidate whether there is a common mechanism underlying the involvement of PTP-Bas/BL in these different systems. Focusing on splice variant specific interactions as well as identifying major substrates for the protein tyrosine phosphatase will lead to a better understanding of this fascinating molecule. Moreover, mice knockout technology and the recently developed siRNA methodology will certainly contribute in identifying the precise molecular functions of PTP-Bas/BL.
This work was supported by a grant from the Deutsche Forschungsgemeinschaft, SFB 452.