Attenuation of Leptin Action and Regulation of Obesity by Protein Tyrosine Phosphatase 1B

Cheng, Alan; Uetani, Noriko; Simoncic, Paul D.; Chaubey, Vikas P.; Lee-Loy, Ailsa; McGlade, C. Jane; Kennedy, Brian P.; Tremblay, Michel L.

doi:10.1016/s1534-5807(02)00149-1

Cited by 497 publications

(415 citation statements)

References 36 publications

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“…When these animals are subjected to the stress of a high fat diet, they show protection against diabetes and obesity through increased phosphorylation of signaling components associated with the insulin, leptin, and growth hormone receptors (12)(13)(14)(15)46). In response to Fas activation, a known stress inducer, we have shown, in PTP1B-null mice but not WT mice, elevated tyrosine phosphorylation and downstream signaling of receptor tyrosine kinases involved in liver injury, namely the Met receptor tyrosine kinase.…”

Section: Discussionmentioning

confidence: 76%

“…PTP1B-null mice show hyperphosphorylation of the insulin receptor in liver and muscle tissue upon stimulation with insulin (12,13). Moreover, these mice are resistant to weight gain caused by a high fat diet through the ability of PTP1B to regulate the leptin receptor, via dephosphorylation and subsequent termination of signaling from the downstream kinase Jak2 (14,15). PTP1B has also been shown to interact with a number of SH3 domain-containing proteins through its proline-rich motifs, including p130Cas (3), p62Dok (16), ␤-catenin (17), Grb2, and Crk (3), which are thought to target this phosphatase to distinct cellular protein complexes.…”

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confidence: 99%

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Protein-tyrosine Phosphatase 1B Deficiency Protects against Fas-induced Hepatic Failure

Sangwan

Paliouras

Cheng

et al. 2006

Journal of Biological Chemistry

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Genetic disruption of protein-tyrosine phosphatase 1B (PTP1B) in mice leads to increased insulin sensitivity and resistance to weight gain. Although PTP1B has been implicated as a regulator of multiple signals, its function in other physiological responses in vivo is poorly understood. Here we demonstrate that PTP1B-null mice are resistant to Fas-induced liver damage and lethality, as evident by reduced hepatic apoptosis in PTP1B-null versus wild type mice and reduced levels of circulating liver enzymes. Activation of pro-apoptotic caspases-8, -9, -3, and -6 was attenuated in livers from PTP1B-null mice following Fas receptor stimulation, although components of the death-inducing signaling complex were intact. Activation of anti-apoptotic regulators, such as the hepatocyte growth factor/Met receptor tyrosine kinase, as well as Raf, ERK1/2, FLIP L , and the NF-B pathway, was elevated in response to Fas activation in livers from PTP1B-null mice. Using PTP1B-deficient primary hepatocytes, we show that resistance to Fas-mediated apoptosis is cell autonomous and that signals involving the Met, ERK1/2, and NF-B pathways are required for cytoprotection. This study identifies a previously unknown physiological role for PTP1B in Fas-mediated liver damage and points to PTP1B as a potential therapeutic target against hepatotoxic agents.

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Section: Discussionmentioning

confidence: 76%

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confidence: 99%

Protein-tyrosine Phosphatase 1B Deficiency Protects against Fas-induced Hepatic Failure

Sangwan

Paliouras

Cheng

et al. 2006

Journal of Biological Chemistry

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“…Of particular interest, gene-targeting studies in mice have established PTP1B as a critical physiological regulator of metabolism by attenuating insulin, leptin, and growth hormone signaling (2)(3)(4)(5)(6). PTP1B function seems to be dispensable for embryonic development.…”

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confidence: 99%

The role of protein tyrosine phosphatase 1B in Ras signaling

Dubé

Cheng

Tremblay

2004

Proc. Natl. Acad. Sci. U.S.A.

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Protein tyrosine phosphatase (PTP) 1B has been implicated as a negative regulator of multiple signaling pathways downstream of receptor tyrosine kinases. Inhibition of this enzyme was initially thought to potentially lead to increased oncogenic signaling and tumorigenesis. Surprisingly, we show that platelet-derived growth factor-stimulated extracellular-regulated kinase signaling in PTP1B-deficient cells is not significantly hyperactivated. Moreover, these cells exhibit decreased Ras activity and reduced proliferation by way of previously uncharacterized pathways. On immortalization, PTP1B-deficient fibroblasts display increased expression of Ras GTPase-activating protein (p120RasGAP). Furthermore, we demonstrate that p62Dok (downstream of tyrosine kinase) is a putative substrate of PTP1B and that tyrosine phosphorylation of p62Dok is indeed increased in PTP1B-deficient cells. Consistent with the decreased Ras activity in cells lacking PTP1B, introduction of constitutively activated Ras restored extracellular-regulated kinase signaling and their proliferative potential to those of WT cells. These results indicate that loss of PTP1B can lead to decreased Ras signaling, despite enhanced signaling of other pathways. This finding may in part explain the absence of increased tumor incidence in PTP1B-deficient mice. Thus, PTP1B can positively regulate Ras activity by acting on pathways distal to those of receptor tyrosine kinases.

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“…Aberrant tyrosine phosphorylation levels have been associated with the development of cancer, autoimmunity, and diabetes, thus indicating that PTPs might play important etiological and pathogenic roles in these diseases (1)(2)(3)(4)(5). In particular, two elegant studies with PTP1B knockout mice, in which increased insulin sensitivity and resistance to diet-induced obesity were observed (6,7), indicated that PTP1B is an important negative regulator of insulin and leptin action, suggesting that inhibition of this enzyme could augment and prolong insulin and leptin signaling (8,9). As a result, a number of academic and industrial laboratories have devoted considerable efforts toward the development of selective inhibitors of PTP1B for treatment of type 2 diabetes and obesity resulting in very significant progress (reviewed in Refs.…”

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Structure-based Design of Selective and Potent Inhibitors of Protein-tyrosine Phosphatase β

Lund

Andersen

Iversen

et al. 2004

Journal of Biological Chemistry

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Protein-tyrosine phosphatases (PTPs) are considered important therapeutic targets because of their pivotal role as regulators of signal transduction and thus their implication in several human diseases such as diabetes, cancer, and autoimmunity. In particular, PTP1B has been the focus of many academic and industrial laboratories because it was found to be an important negative regulator of insulin and leptin signaling, and hence a potential therapeutic target in diabetes and obesity. As a result, significant progress has been achieved in the design of highly selective and potent PTP1B inhibitors. In contrast, little attention has been given to other potential drug targets within the PTP family. Guided by x-ray crystallography, molecular modeling, and enzyme kinetic analyses with wild type and mutant PTPs, we describe the development of a general, low molecular weight, non-peptide, non-phosphorus PTP inhibitor into an inhibitor that displays more than 100-fold selectivity for PTP␤ over PTP1B. Of note, our structure-based design principles, which are based on extensive bioinformatics analyses of the PTP family, are general in nature. Therefore, we anticipate that this strategy, here applied to PTP␤, in principle can be used in the design and development of selective inhibitors of many, if not most PTPs.Protein-tyrosine phosphatases (PTPs) 1 are key regulators of signal transduction. Together with the counteracting proteintyrosine kinases, they control the phosphorylation status of many important proteins and are thereby critically involved in the regulation of fundamental cellular processes such as metabolism, cell growth, and differentiation. Aberrant tyrosine phosphorylation levels have been associated with the development of cancer, autoimmunity, and diabetes, thus indicating that PTPs might play important etiological and pathogenic roles in these diseases (1-5). In particular, two elegant studies with PTP1B knockout mice, in which increased insulin sensitivity and resistance to diet-induced obesity were observed (6, 7), indicated that PTP1B is an important negative regulator of insulin and leptin action, suggesting that inhibition of this enzyme could augment and prolong insulin and leptin signaling (8, 9). As a result, a number of academic and industrial laboratories have devoted considerable efforts toward the development of selective inhibitors of PTP1B for treatment of type 2 diabetes and obesity resulting in very significant progress (reviewed in Refs. 10 -12). The field has advanced significantly by a number of x-ray crystallographic structures (reviewed in Refs. 3, 13, and 14), and several research groups have successfully used structure-based designs to synthesize active site-directed, selective PTP1B inhibitors (15-20). Most important, two groups have demonstrated recently that it is possible to develop compounds that are selective for PTP1B over the highly homologous T cell-PTP (21, 22), thereby lending support to the view that selective inhibitors, which discriminate between even closely related PTP...

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Attenuation of Leptin Action and Regulation of Obesity by Protein Tyrosine Phosphatase 1B

Cited by 497 publications

References 36 publications

Protein-tyrosine Phosphatase 1B Deficiency Protects against Fas-induced Hepatic Failure

Protein-tyrosine Phosphatase 1B Deficiency Protects against Fas-induced Hepatic Failure

The role of protein tyrosine phosphatase 1B in Ras signaling

Structure-based Design of Selective and Potent Inhibitors of Protein-tyrosine Phosphatase β

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