• insulin resistance;
  • insulin receptor;
  • insulin signaling;
  • protein tyrosine phosphatase;
  • PTP1B glucose homeostasis;
  • TCPTP;
  • type 2 diabetes;
  • tyrosine phosphorylation


  1. Top of page
  2. Abstract
  3. Insulin resistance
  4. Insulin signaling
  5. PTP1B and insulin signaling
  6. PTP1B and diabetes
  7. TCPTP
  8. TCPTP and PTP1B are not redundant
  9. TCPTP and insulin signaling
  10. Perspectives
  11. Acknowledgements
  12. References

Insulin resistance is a key pathological feature of type 2 diabetes and is characterized by defects in signaling by the insulin receptor (IR) protein tyrosine kinase. The inhibition of protein tyrosine phosphatases (PTPs) that antagonize IR signaling may provide a means for enhancing the insulin response and alleviating insulin resistance. The prototypic phosphotyrosine-specific phosphatase PTP1B dephosphorylates the IR and attenuates insulin signaling in muscle and liver. Mice that are deficient for PTP1B exhibit improved glucose homeostasis in diet and genetic models of insulin resistance and type 2 diabetes. The phosphatase TCPTP shares 72% catalytic domain sequence identity with PTP1B and has also been implicated in IR regulation. Despite their high degree of similarity, PTP1B and TCPTP act together in vitro and in vivo to regulate insulin signaling and glucose homeostasis. This review highlights their capacity to act specifically and nonredundantly in cellular signaling, describes their roles in IR regulation and glucose homeostasis, and discusses their potential as drug targets for the enhancement of IR phosphorylation and insulin sensitivity in type 2 diabetes.


endoplasmic reticulum


insulin receptor


IR substrate


mouse embryo fibroblast


phosphatidylinositol 3-kinase


protein tyrosine kinase


protein tyrosine phosphatase


T-cell PTP


white adipose tissue

Insulin resistance

  1. Top of page
  2. Abstract
  3. Insulin resistance
  4. Insulin signaling
  5. PTP1B and insulin signaling
  6. PTP1B and diabetes
  7. TCPTP
  8. TCPTP and PTP1B are not redundant
  9. TCPTP and insulin signaling
  10. Perspectives
  11. Acknowledgements
  12. References

The incidence of type 2 diabetes has reached epidemic proportions and has become one of the world’s most common diseases [1,2]. Current therapeutic approaches are not adequate to deal with the underlying driving factors of this disease, or the associated complications, and there is an urgent need to develop novel strategies. A key feature of type 2 diabetes is diminished insulin responsiveness, so-called insulin resistance, in peripheral (liver, muscle, fat) and central (hypothalamus) tissues. Insulin resistance is associated with compensatory hyperinsulinemia and at first normal glucose tolerance, but progresses to impaired glucose tolerance and ultimately frank type 2 diabetes characterized by defective insulin secretion and overt hyperglycemia [3,4]. Insulin resistance in the glucose-tolerant state is associated with defects or aberrations in signaling downstream of the insulin receptor (IR) protein tyrosine kinase (PTK) [3–7]. In more advanced disease, characterized by glucose intolerance, insulin resistance is also associated with decreased IR tyrosine phosphorylation; the decrease in IR tyrosine phosphorylation cannot be explained by decreased IR cell surface levels or insulin binding [3,8–10]. Protein tyrosine phosphatases (PTPs) are key negative regulators of IR signaling serving to dephosphorylate the tyrosine-phosphorylated IR and downstream substrates to terminate insulin action [11–14]. Studies in rodents and humans have shown that PTPs that attenuate insulin signaling are elevated in insulin target tissues in obesity/type 2 diabetes [11–14]. One approach for enhancing insulin sensitivity and alleviating insulin resistance, both early and late in disease progression, might involve the inhibition of PTPs that otherwise dephosphorylate and inactivate the IR [15,16].

Insulin signaling

  1. Top of page
  2. Abstract
  3. Insulin resistance
  4. Insulin signaling
  5. PTP1B and insulin signaling
  6. PTP1B and diabetes
  7. TCPTP
  8. TCPTP and PTP1B are not redundant
  9. TCPTP and insulin signaling
  10. Perspectives
  11. Acknowledgements
  12. References

Insulin acts on the liver and brain to turn off hepatic glucose production and to promote glycogen synthesis and lipogenesis, and on muscle and fat, to promote the uptake of glucose and its storage as glycogen and triglycerides respectively [3,4,17]. Insulin resistance in the liver and the brain and the consequent defective suppression of hepatic glucose production, is responsible for the hyperglycemia in the fasted state, whereas muscle insulin resistance is primarily responsible for the defective insulin-stimulated glucose disposal in type 2 diabetes [3,4,17]. Insulin elicits its effects by activating the IR, a transmembrane PTK that phosphorylates itself as well target substrates such as IR substrate (IRS)-1 and -2 [3,18]. Upon binding insulin, the IR undergoes transphosphorylation on several sites including the Y1162/Y1163 β-subunit PTK activation loop site; Y1162/Y1163 phosphorylation is required for IR activation and the phosphorylation of other sites, including the juxtamembrane Y972 site that allows for the recruitment of IRS-1 [3,18,19]. IRS-1/2 tyrosine phosphorylation events, in turn, allow for the recruitment of Src homology 2 domain-containing proteins, including the p85 regulatory subunit of phosphatidylinositol 3-kinase (PtdIns3K). p85 recruitment results in PtdIns3K activation, the generation of lipid products and the activation of protein kinases including Akt and downstream mTOR and p70S6K that mediate the metabolic actions of insulin [3,18,20]. In particular, PtdIns3K signaling and Akt2 are thought to be essential for the translocation and docking of the GLUT4 glucose transporter on the plasma membrane in muscle and fat [3,20–23]. Other proteins with Src homology 2 domains that are recruited to IRS-1/2 include the adaptor proteins Grb2 and p52Shc, which activate the Ras/mitogen-activated protein kinase pathway that mediates the mitogenic actions of insulin [3,18]. Under conditions of insulin resistance, PtdIns3K signaling is attenuated, but the mitogen-activated protein kinase pathway remains unperturbed [7]. A widely accepted mechanism for the defect in PtdIns3K signaling involves Ser/ Thr phosphorylation of IRS-1, by the protein kinases c-jun N-terminal kinase, protein kinase C and IκB kinase β, to attenuate p85 recruitment and thus PtdIns3K activation [24–29].

PTP1B and insulin signaling

  1. Top of page
  2. Abstract
  3. Insulin resistance
  4. Insulin signaling
  5. PTP1B and insulin signaling
  6. PTP1B and diabetes
  7. TCPTP
  8. TCPTP and PTP1B are not redundant
  9. TCPTP and insulin signaling
  10. Perspectives
  11. Acknowledgements
  12. References

PTPs are key negative regulators of IR signaling and their inhibition with broad-based pharmacological inhibitors can mimic several actions of insulin including the promotion of glucose uptake and the inhibition of lipolysis [11,12,30]. PTPs dephosphosphorylate the tyrosine-phosphorylated IR and the downstream IRS-1/2 proteins within minutes of insulin stimulation to inactivate and terminate IR signaling [11–14]. The prototypic endoplasmic reticulum (ER)-targeted ubiquitous protein tyrosine phosphatase 1B (PTP1B) [31–36] is a major IR phosphatase in liver and muscle [34,35,37–39]. PTP1B binds to and dephosphorylates the IR in vitro and PTP1B ‘substrate-trapping’ mutants (C215S or D182A) can form stable complexes with the tyrosine-phosphorylated IR in a cellular context [40–45]. Moreover, ectopic expression of wild-type PTP1B in cells can inhibit IR activation and function [44,46–50], whereas PTP1B neutralization or inhibition, or knockdown of PTP1B expression can stimulate insulin signaling and alleviate insulin resistance [41,48,51–55]. Definitive evidence for PTP1B’s role in insulin signaling in vivo came from Elchebly et al. [34] and Klaman et al. [35], who independently generated and characterized PTP1B-null (Ptpn1−/−) mice. Ptpn1−/− mice exhibited both increased insulin sensitivity and attenuated diet-induced obesity and insulin resistance [34,35]. The enhanced insulin sensitivity in Ptpn1−/− mice was associated with increased IR activation and downstream IRS-1 tyrosine phosphorylation in liver and muscle [34,35]. In subsequent studies, the obesity resistance in Ptpn1−/− mice was ascribed to enhanced leptin sensitivity and elevated hypothalamic JAK2/STAT3 signaling [38,56,57]. Although the obesity resistance in Ptpn1−/− mice undoubtedly impacts on glucose homeostasis, PTP1B’s direct regulation of IR activation and signaling in muscle and liver has been substantiated by studies reconstituting (adenoviral) PTP1B into the livers of Ptpn1−/− mice and by the generation of liver- and muscle-specific PTP1B-deficient mice [37–39]. Furthermore, recent studies have shown that obese Ptpn1−/− mice on the leptin receptor-deficient (db/db) background have similar body weights, but exhibit improved glucose clearance and reduced hemoglobin A1c levels and enhanced IR phosphorylation in muscle [58]. Thus, PTP1B can regulate glucose homeostasis independently of body weight.

PTP1B may also have an important role in regulating insulin sensitivity in ‘nonconventional’ insulin-responsive tissues. Conditional deletion of PTP1B in the mouse retina enhances IR activation and PtdIns3K/Akt signaling to promote cell survival and protect photoreceptor cells from bright-light-induced degeneration [59]. In brown adipose tissue, a major site for nonshivering thermogenesis and energy expenditure [60], PTP1B may play an important role in insulin signaling and brown adipocyte differentiation and survival [61,62]. Insulin signaling is elevated in PTP1B-deficient brown adipose tissue pre-adipocytes and differentiation is enhanced in vitro in the absence of PTP1B [61,62]. Insulin signaling is important in brown adipose tissue adipogenesis [63,64], but it remains unclear whether brown adipose tissue is altered in Ptpn1−/− mice. Finally, PTP1B has also been implicated in IR regulation in the hypothalamus [65], where insulin signaling is particularly important in the peripheral control of hepatic glucose production and white adipose tissue (WAT) lipogenesis [17,66,67]. Suppressing PTP1B expression in the hypothalami of rats by delivering antisense oligonucleotides into the third lateral ventricle enhances central IR activation and signaling and promotes satiety [65]. Thus, PTP1B regulates IR signaling in different cell types and tissues to control varied physiological and pathological responses.

Although the data implicating PTP1B in IR regulation in peripheral tissues are compelling, it is clear that additional PTPs dephosphorylate the IR in vivo. First, even in the absence of PTP1B, the IR is eventually dephosphorylated and inactivated in muscle or liver [34,35]. Second, IR phosphorylation and glucose uptake into WAT are not altered in Ptpn1−/− mice [34,35], consistent with an altogether different PTP being responsible for IR dephosphorylation in WAT. The ER-localized PTP1B is believed to dephosphorylate the IR only after it is endocytosed [68,69]. One possible reason for the tissue-specific contributions of PTP1B to IR regulation may be that IR trafficking in adipocytes may be different and the IR may be inaccessible to the ER-localized PTP1B. However, this does not appear to be the case, because elevated PTP1B expression in WAT, as occurs in obese db/db mice, can suppress IR tyrosine phosphorylation [58]. Hence, these results are consistent with other PTPs compensating for PTP1B deficiency in WAT. Interestingly, WAT-specific PTP1B-deficient mice exhibit increased adiposity [38], suggesting that PTP1B may promote WAT lipogenesis and/or adipogenesis by alternate means.

PTP1B and diabetes

  1. Top of page
  2. Abstract
  3. Insulin resistance
  4. Insulin signaling
  5. PTP1B and insulin signaling
  6. PTP1B and diabetes
  7. TCPTP
  8. TCPTP and PTP1B are not redundant
  9. TCPTP and insulin signaling
  10. Perspectives
  11. Acknowledgements
  12. References

Whole-body, or muscle- or liver-specific PTP1B deficiency can alleviate insulin resistance and improve glucose homeostasis in obese mice [34,35,37–39]. Moreover, PTP1B deficiency can improve insulin sensitivity and glucose tolerance in IRS-2−/− mice [70] that otherwise display hepatic insulin resistance and β-cell failure [71]. Indeed, PTP1B is elevated in hepatocytes in IRS-2−/− mice and PTP1B deletion restores hepatic insulin-induced PtdIns3K/Akt signaling via IRS-1 to suppress hepatic gluconeogenic gene expression [72]. PTP1B deficiency in IRS-2−/− mice also delays β-cell failure and the onset of diabetes [70]. Furthermore, PTP1B deficiency markedly improves glucose tolerance and insulin sensitivity and decreases the incidence of β-cell hyperplasia and the development of diabetes in mice with a double heterozygous deficiency in IR and IRS-1 [73]. This is associated with enhanced insulin signaling in liver and muscle and importantly occurs independent of changes in body weight and adiposity [73]. Furthermore, resveratrol-induced and SIRT1-mediated repression of PTPN1 transcription and consequent PTP1B protein levels in high-fat-fed insulin-resistant mice, enhances IR tyrosine phosphorylation and signaling and improves insulin sensitivity and glucose tolerance [74]. Therefore, there is compelling evidence for PTP1B deficiency or inhibition alleviating insulin resistance in type 2 diabetes.

Conversely, increased PTP1B expression in peripheral tissues can attenuate the insulin signal and contribute to insulin resistance in rodents and humans. PTP1B expression and activity are increased in the muscle and adipose tissue of obese and insulin-resistant humans and in rodent models of obesity and type 2 diabetes [15,58,75–78]. ER stress and inflammatory cytokines such as tumor necrosis factor (TNF) have been linked with the stimulation of PTP1B expression in liver, muscle, fat and the hypothalamus for the promotion of insulin and leptin resistance [78,79]. Increased PTP1B expression under conditions of insulin resistance has also been linked with decreased levels of the histone deacetylase SIRT1 that otherwise represses PTPN1 transcription [74]. In keeping with increased PTP1B levels being causal in the promotion of insulin resistance, transgenic overexpression of PTP1B alone in muscle is sufficient to cause insulin resistance and defective whole-body glucose disposal in mice [80]. Finally, single nucleotide polymorphisms (SNPs) in PTPN1 have been linked with an increased susceptibility to type 2 diabetes in different populations [81,82]; at least one of these SNPs may result in increased PTPN1 mRNA stability [83].

Given PTP1B’s important roles in peripheral insulin sensitivity and central leptin sensitivity, there is considerable interest in PTP1B as a target for the development of novel therapeutics for the treatment of type 2 diabetes and obesity. Preclinical studies utilizing antisense oligonucleotides that suppress PTP1B expression in liver and fat have demonstrated that PTP1B inhibition can enhance insulin sensitivity and normalize blood glucose levels in rodent models of insulin resistance [84–86], therefore validating PTP1B as a therapeutic target for the treatment of type 2 diabetes. Antisense oligonucleotides targeting PTP1B (ISIS  113715; ISIS Pharmaceuticals, Carlsbad, CA, USA) have shown favorable outcomes in terms of glucose control and lowering low-density lipoprotein cholesterol (as reported by ISIS Pharmaceuticals; A range of PTP1B inhibitors that act via the PTP active site or allosteric regulatory sites are also in preclinical development [15,16,87], whereas naturally occurring agents, such as berberine and resveratrol that have beneficial metabolic effects, exert at least some of their effects on insulin signaling and glucose control via the inhibition or repression of PTP1B [74,88,89]. Recent studies have shown that resveratrol supplementation for 30 days elicits metabolic changes in obese humans, lowering blood glucose and triglycerides and improving the HOMA [90] index, consistent enhanced insulin sensitivity. Such studies have vindicated the concerted efforts underway worldwide in academia and industry to develop PTP1B inhibitors for the treatment of type 2 diabetes and the metabolic syndrome in general.


  1. Top of page
  2. Abstract
  3. Insulin resistance
  4. Insulin signaling
  5. PTP1B and insulin signaling
  6. PTP1B and diabetes
  7. TCPTP
  8. TCPTP and PTP1B are not redundant
  9. TCPTP and insulin signaling
  10. Perspectives
  11. Acknowledgements
  12. References

TCPTP (encoded by PTPN2) is one of 38 classical tyrosine-specific PTPs encoded by the human genome. TCPTP, short for T-cell PTP, was so called because it was originally cloned from a T-cell cDNA library [36,91]. Although TCPTP is abundant in cells of hematopoietic origin, it is a ubiquitous phosphatase that is expressed in all tissues and cell types and at all stages of development [36]. Two variants of TCPTP are expressed that arise from alternative splicing of PTPN2 message: a 48 kDa form, which like PTP1B is targeted to the ER by a hydrophobic C-terminus, and a 45 kDa variant that lacks the hydrophobic C-terminus and is targeted to the nucleus by a bipartite nuclear localization sequence [36] (Fig. 1). Despite an apparent exclusive nuclear localization in resting cells, the 45 kDa TCPTP can exit the nucleus in response to varied stimuli, including insulin, to access substrates in the cytoplasm and at the plasma membrane [36,92–94]. TCPTP substrates include: (a) receptor PTKs such as the IR [92,95,96], the epidermal growth factor receptor (ErbB1) [94,97–99], the platelet-derived growth factor receptor [100] and the hepatocyte growth factor receptor (c-Met) [101]; (b) nonreceptor PTKs such as c-Src, Fyn, Lck [102–105] and JAK-1 and -3 [106]; and (c) PTK substrates such as p52Shc [94] and STAT-1, -3, -5 and -6 [95,104,107–109]. Accordingly, TCPTP has the capacity to regulate varied signaling pathways and biological processes.


Figure 1.  Schematic representation of PTP1B and the 45 kDa and 48 kDa TCPTP variants. The PTP catalytic and the noncatalytic C-terminal domains of PTP1B and TCPTP are shown highlighting the high degree of catalytic domain primary sequence conservation. The PTP1B PXXPXR motif that allows for interaction with Src homology 3 domain-containing proteins and the hydrophobic C-terminal tail targeting PTP1B to the ER are shown, as is the corresponding hydrophobic ER-targeting sequence in the 48 kDa TCPTP. Also shown is the bipartite nuclear localization sequence (NLS) in TCPTP that targets the 45 kDa TCPTP to the nucleus.

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The generation of mice globally deficient for TCPTP (Ptpn2−/−) [110] has highlighted in particular TCPTP’s key role in the hematopoietic compartment. In contrast to PTP1B null mice (on a C57BL/6 background) that have a normal lifespan and exhibit decreased adiposity and increased insulin sensitivity [34,35], Ptpn2−/− (on a mixed BALB/c-129SJ background) mice die soon after birth from severe anemia, hematopoietic defects and the development of progressive systemic inflammatory disease, characterized by increases in circulating proinflammtory cytokines and lymphocytic infiltrates in nonlymphoid tissues [110,111]. Ptpn2−/− mice appear physically normal, albeit slightly smaller, at 10–14 days of age, but thereon exhibit growth retardation, a hunched posture, piloerection, decreased mobility and diarrhea, succumbing by 3–5 weeks of age [110]. The morbidity and mortality and the hematopoietic defects and anemia in Ptpn2−/− mice may be attributable to bone marrow stromal cell abnormalities [110,112], but further studies are necessary to elucidate the precise cellular and molecular bases for the disease and lethality. The recently generated Ptpn2 floxed mice promise to be a valuable resource for defining TCPTP’s cell type- and tissue-specific contributions to biology and disease [54,103,105]. For example, T-cell-specific TCPTP-deficient mice (on a C57BL/6 background) have been used recently to establish that at least part of the inflammatory phenotype in Ptpn2−/− mice may be ascribed to enhanced T-cell receptor signaling and T-cell activation [105].

TCPTP and PTP1B are not redundant

  1. Top of page
  2. Abstract
  3. Insulin resistance
  4. Insulin signaling
  5. PTP1B and insulin signaling
  6. PTP1B and diabetes
  7. TCPTP
  8. TCPTP and PTP1B are not redundant
  9. TCPTP and insulin signaling
  10. Perspectives
  11. Acknowledgements
  12. References

The catalytic domains of PTP1B and TCPTP share a high degree of primary (72% identity and 86% similarity; TCPTP residues 43–288) and tertiary structure similarity and have similar active sites [36,113] (Fig. 1). PTP1B and TCPTP are among the most closely related of the classical phosphotyrosine-specific PTPs, with members of this enzyme subfamily in general sharing an approximate 35% sequence identity [36,113]. In particular, both PTPs share a second ‘phosphotyrosine-binding pocket’ that allows for the selective recognition of substrates phosphorylated on tandem tyrosines [94,114,115], such as the IR β-subunit activation loop Y1162/Y1163 phosphorylation site [92,96,114] (Fig. 2), or the JAK1/2/3 and TYK2 activation loop (Y1022/Y1023 in JAK1; Y1007/Y1008 in JAK2; Y980/Y981 in JAK3; Y1054/Y1055) phosphorylation sites [56,106,116]. Despite their similarity, TCPTP and PTP1B exhibit a high degree of substrate selectivity in a cellular context. This substrate selectivity is evident in the distinct phenotypes of Ptpn1−/− versus Ptpn2−/− mice [34,35,110] and substantiated by extensive molecular and substrate identification studies. For example, PTP1B can dephosphorylate JAK2, but not JAK1/3, whereas TCPTP dephosphorylates JAK1/3, but not JAK2 [56,106,116]. Moreover, PTP1B and TCPTP dephosphorylate distinct platelet-derived growth factor receptor tyrosine phosphorylation sites to differentially control signaling and cell migration/chemotaxis [100]. Their unique substrate selectivities are highlighted in particular by their opposing roles in the regulation of Src family PTKs. PTP1B dephosphorylates the c-Src C-terminal Y529 (Y527 avian) inhibitory phosphorylation site to activate c-Src [117,118], whereas TCPTP dephosphorylates the c-Src Y418 (Y416 avian) PTK activation loop site to inactivate c-Src [102]. PTP1B’s ability to dephosphorylate the c-Src Y529 site is dependent on a noncatalytic C-terminal domain proline-rich sequence that can interact with proteins containing N-terminal Src homology 3 domains [119–122]; this proline-rich sequence is not present in TCPTP (Fig. 1). Their differential contributions to SFK regulation is evident in TNF signaling, where PTP1B promotes and TCPTP attenuates TNF-induced and mitogen-activated protein kinase-mediated inflammatory responses [102,123,124], and in pancreatic β cells, where high-fat-diet-induced increases in PTP1B and decreases in TCPTP serve to promote SFK activation and attenuate ER stress [125]. Furthermore, PTP1B and TCPTP function cooperatively to regulate the intensity and duration of IR activation and signaling by coordinately regulating Y1162/Y1163 phosphorylation [92,96,126] and also work in concert to regulate MET receptor phosphorylation [101]. PTP1B and TCPTP also promote distinct effects on signaling by virtue of their different subcellular locations [36]. For example, both PTP1B and 45 kDa TCPTP can directly regulate STAT6 Y641 phosphorylation, but exert their effects in the cytoplasm and nucleus respectively [127,128]. Importantly, recent studies have highlighted that their substrate specificity, selectivity and cooperativity extend in vivo in the central control of body weight and glucose homeostasis, where PTP1B attenuates hypothalamic leptin signaling at the level of JAK2 (but not STAT3 or the leptin receptor [57]) in the cytoplasm, and TCPTP dephosphorylates STAT3 in the nucleus [56,103,106,116] (Fig. 2). These studies have shown that conditional deletion of PTP1B and TCPTP in neuronal and glial cells has additive effects in the promotion of central leptin sensitivity and in the attenuation of high-fat-diet-induced obesity and the concomitant development of insulin resistance and glucose intolerance [103]. These studies have served to highlight the nonredundant and essential nature of even highly related phosphatases in vivo. Moreover, these studies have underscored the potential of combinatorially inhibiting PTP1B and TCPTP in the hypothalamus for the prevention of obesity and the improvement of whole-body glucose homeostasis.


Figure 2.  PTP1B and TCPTP in insulin and leptin signaling. Schematic representation of the functions of PTP1B and the 45 kDa and 48 kDa variants of TCPTP on insulin and leptin signaling in the liver and hypothalamus, respectively. PTP1B and TCPTP dephosphorylate the IRβ Y1162/Y1663 PTK activation loop phosphorylation site to attenuate insulin signaling. The 45 kDa TCPTP variant can exit the nucleus in response to insulin to dephosphorylate IRβ at the plasma membrane and cytoplasm, whereas PTP1B and the 48 kDa TCPTP variant dephosphorylate IRβ after the receptor is endocytosed. PTP1B and TCPTP also act together to regulate leptin signaling with PTP1B dephosphorylating JAK2 in the cytoplasm and the 45 kDa TCPTP dephosphorylating STAT3 in the nucleus.

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TCPTP and insulin signaling

  1. Top of page
  2. Abstract
  3. Insulin resistance
  4. Insulin signaling
  5. PTP1B and insulin signaling
  6. PTP1B and diabetes
  7. TCPTP
  8. TCPTP and PTP1B are not redundant
  9. TCPTP and insulin signaling
  10. Perspectives
  11. Acknowledgements
  12. References

Previous studies have established that the IR can serve as a cytoplasmic substrate for TCPTP in vitro and in vivo [92,95,96]. Using TCPTP–D182A ‘substrate-trapping’ mutants [36,94,129] Galic et al. [92,96] have shown that TCPTP has the capacity to recognize the tyrosine-phosphorylated IR as cellular substrate [92] (Fig. 2). Whereas the 45 kDa TCPTP exits the nucleus in response to insulin to dephosphorylate the IR at the plasma membrane and cytoplasm [92], the ER-targeted 48 kDa TCPTP may dephoshorylate the IR after it has been endocytosed, as has been shown previously for PTP1B’s regulation of ErbB1 [68] (Fig. 2). Consistent with TCPTP dephosphorylating the IR, insulin-induced IR β-subunit (IRβ) Y1162/Y1163 phosphorylation and PtdIns3K/Akt signaling are increased in TCPTP-deficient immortalized mouse embryo fibroblasts (MEFs) and in HepG2 hepatoma cells after TCPTP knockdown by RNA interference [92,126]. In line with TCPTP being an important regulator of IR signaling in vivo, Fukushima et al. [95] have established that IRβ Y1162/Y1163 phosphorylation and signaling are elevated in hepatocytes derived from Ptpn2+/− mice and that TCPTP heterozygous deficiency enhances hepatic PtdIns3K/Akt signaling and suppresses gluconeogenesis and hepatic glucose output to prevent the fasting hyperglycemia that is otherwise associated with development of insulin resistance in high-fat-fed mice [95]. As highlighted above, PTP1B is also an important negative regulator hepatic IR signaling and mice that lack PTP1B in hepatocytes exhibit significantly enhanced insulin-induced IRβ Y1162/Y1163 phosphorylation and signaling, enhanced suppression of hepatic glucose production and protection from high-fat-diet-induced glucose intolerance [39]. Conversely hepatic PTP1B re-expression in Ptpn1−/− mice suppresses insulin-induced IR activation and signaling [37]. Interestingly hepatic PTP1B deficiency also results in decreased lipogenic gene expression in the fasted state and protects mice from high-fat-diet-induced ER stress [39,79], which can otherwise promote insulin resistance. As in the pancreas, ER stress promotes PTP1B expression in the liver, but in this instance, PTP1B expression may exacerbate ER stress signaling [39,79,125]. In contrast to hepatic PTP1B deficiency, TCPTP heterozygous deficiency does not alter lipogenic gene expression in fasted mice [95]. Similarly, high-fat-fed male liver-specific TCPTP-deficient mice do not exhibit any overt changes in lipogenic gene expression (unpublished observations). Therefore, TCPTP and PTP1B differentially contribute to lipogenesis in the liver. It remains to be seen if TCPTP modulates the ER stress response in the liver.

PTP1B and TCPTP can function in the same cell to regulate IR signaling. Indeed, both PTP1B and TCPTP can be transiently oxidized by reactive oxygen species in fibroblasts in response to insulin stimulation [126]; reactive oxygen species inactivate PTPs to facilitate PTK signaling (for a review on reactive oxygen species regulation of PTPs see [130]). Interestingly, whereas PTP1B may serve to regulate the intensity or amplitude of IR activation and signaling, TCPTP may be more important in controlling the duration of insulin signaling [96] (Fig. 3). MEFs lacking PTP1B exhibit a significant enhancement in insulin-induced IRβ Y1162/Y1163 phosphorylation and PtdIns3K/Akt signaling, but the duration of signaling is largely unaltered, waning by 30–45 min [96] (Fig. 3). By contrast, the amplitude of IRβ Y1162/Y1163 phosphorylation and signaling are not altered in TCPTP-deficient MEFs, but instead IRβ Y1162/Y1163 phosphorylation and PtdIns3K/Akt signaling are sustained for many hours [92,96]. Importantly, knockdown of TCPTP expression by RNA interference in PTP1B-deficient MEFs results in both elevated and sustained signaling [96] (Fig. 3), establishing the capacity of PTP1B and TCPTP to function coordinately in the temporal control of insulin-induced responses. Recent findings suggest that the differential contributions of PTP1B and TCPTP to the intensity and duration of IR signaling may also be pertinent in vivo. Although bolus insulin administration results in a significant increase in hepatic IRβ Y1162/Y1163 phosphorylation and PtdIns3K/Akt signaling in mice lacking PTP1B in the liver [39], this is not evident in mice with global TCPTP heterozygous deficiency [95]. Instead, TCPTP deficiency may prolong hepatic IR activation and signaling (as assessed in mice that have been fasted re-fed, and then re-fasted [95]). Delineating the precise molecular mechanisms by which PTP1B and TCPTP may differentially contribute to the temporal control of IR signaling will require further study.


Figure 3.  PTP1B and TCPTP regulate the intensity and duration of insulin signaling. Schematic representation of insulin signaling in PTP1B (Ptpn1−/−)-, TCPTP (Ptpn2−/−)- and PTP1B/TCPTP (Ptpn1−/−; Ptpn2 siRNA knockdown)-deficiency in MEFs. PTP1B-deficiency enhances IRβ Y1162/Y1663 phosphorylation and downstream PtdIns3K/Akt signaling, TCPTP deficiency results in prolonged signaling, whereas a combined deficiency in PTP1B and TCPTP results in both enhanced and prolonged IRβ Y1162/Y1663 phosphorylation and PtdIns3K/Akt signaling.

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Although TCPTP may have a role in IR regulation in the liver, this does not extend to muscle. In contrast to PTP1B deficiency, which results in increased IR activation and glucose uptake in muscle and increases whole-body insulin sensitivity [131], mice that lack TCPTP specifically in muscle do not exhibit any obvious alterations in insulin sensitivity [54]. Insulin-induced IRβ Y1162/Y1163 phosphorylation and signaling are not altered in gastrocnemius muscle in vivo, or in myoblasts from muscle-specific TCPTP-deficient mice in vitro, and insulin-induced muscle glucose uptake ex vivo and whole-body insulin sensitivity and glucose tolerance are not altered by TCPTP deficiency, either in chow-, or high-fat-fed mice [54]. It is unlikely that this lack of effect on IR signaling in muscle can be ascribed to a functional redundancy with PTP1B, because TCPTP inhibition with a specific pharmacological inhibitor does not enhance insulin signaling in myoblasts when PTP1B is inhibited at the same time [54]. Instead, we suggest that the differential contributions of TCPTP to IR signaling in liver and muscle may reflect the differential expression of the 45 kDa and 48 kDa TCPTP variants, because the 45 kDa variant is expressed more abundantly in liver [95]. Despite the 45 kDa variant being targeted to the nucleus, it can exit the nucleus and may gain unfettered access to substrates in different cytoplasmic compartments [36,93,94]. By contrast, the ER-restricted 48 kDa variant may have limited access to substrates [36,94]. Although both TCPTP variants have the capacity to regulate the IR in vitro, we have shown previously that the two variants can also access distinct substrates [36,94]. It would be of interest to determine if the TCPTP variants differentially contribute to IR regulation and glucose homeostasis in vivo.


  1. Top of page
  2. Abstract
  3. Insulin resistance
  4. Insulin signaling
  5. PTP1B and insulin signaling
  6. PTP1B and diabetes
  7. TCPTP
  8. TCPTP and PTP1B are not redundant
  9. TCPTP and insulin signaling
  10. Perspectives
  11. Acknowledgements
  12. References

Although PTP1B and TCPTP are highly related in sequence and structure, they exhibit striking substrate selectivity in a cellular context and serve to cooperatively regulate signaling. This cooperativity is illustrated in particular by recent studies establishing their nonredundant roles in the central control of body weight and their potential as combinatorial therapeutic targets for the promotion of central leptin sensitivity and the prevention of diet-induced obesity [103]. Although the selective delivery of PTP1B and TCPTP inhibitors to the brain remains a challenge, it is possible that the combined inhibition of PTP1B and TCPTP in peripheral tissues, such as the liver, where both PTPs regulate IR signaling and glucose homeostasis [39,95], may prove useful in enhancing insulin sensitivity and preventing the fasting hyperglycemia that is associated with type 2 diabetes. Moreover, it will be interesting to determine whether TCPTP compensates for PTP1B in adipocytes and whether inhibiting TCPTP in WAT might be of additional benefit.

Unlike PTP1B, genome-wide association studies have not linked PTPN2 SNPs with either type 2 diabetes or obesity in humans, but rather with the development of autoimmune disorders, in particular type 1 diabetes and Crohns disease [132–134]. Moreover, TCPTP expression is not increased in liver, muscle, or fat in high-fat-fed mice [103] arguing against perturbations in TCPTP directly contributing to the development of insulin resistance and type 2 diabetes. However, hypothalamic TCPTP expression is increased in high-fat-fed mice and this is driven by the hyperleptinemia [103] that develops as a consequence of the increased adiposity and the developing leptin resistance. The increased TCPTP attenuates leptin signaling exacerbating leptin resistance and progression towards morbid obesity [103]. The increased hypothalamic TCPTP levels in high-fat-fed mice have highlighted TCPTP’s potential to contribute to obesity, but it remains to be seen if TCPTP is similarly altered in primates.

Ultimately, TCPTP’s role in the immune compartment may limit any approach aimed at targeting TCPTP for the treatment of type 2 diabetes and obesity. However, it is important to stress that the hematopoietic defects and the overt inflammatory phenotype associated with global TCPTP deficiency, or the autoimmunity evident in T-cell-specific TCPTP knockout mice, have been observed in the context of deleting TCPTP early in development [105,110]. Therefore, it will be important to assess the severity of any immune compartment perturbations evident when TCPTP is deleted or inhibited in adult mice. Although TCPTP heterozygous deficiency does not result in any overt immune phenotype [110] and may be beneficial in the context of type 2 diabetes [95], achieving a corresponding level of pharmacological inhibition in a clinical setting would be challenging. Irrespective of whether inhibiting TCPTP will be a viable therapeutic option for type 2 diabetes in the long-term, studies defining PTP1B and TCPTP substrate selectivity and function have provided irrefutable evidence that PTPs can display exquisite specificity in vivo and have highlighted their potential as therapeutic targets for the treatment of a variety human disorders.


  1. Top of page
  2. Abstract
  3. Insulin resistance
  4. Insulin signaling
  5. PTP1B and insulin signaling
  6. PTP1B and diabetes
  7. TCPTP
  8. TCPTP and PTP1B are not redundant
  9. TCPTP and insulin signaling
  10. Perspectives
  11. Acknowledgements
  12. References

TT is a National Health and Medical Research Council (NHMRC) of Australia Principal Research Fellow and supported by grants from the NHMRC.


  1. Top of page
  2. Abstract
  3. Insulin resistance
  4. Insulin signaling
  5. PTP1B and insulin signaling
  6. PTP1B and diabetes
  7. TCPTP
  8. TCPTP and PTP1B are not redundant
  9. TCPTP and insulin signaling
  10. Perspectives
  11. Acknowledgements
  12. References
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