Protein-tyrosine-phosphatase 2C is phosphorylated and inhibited by 44-kDa mitogen-activated protein kinase.

Peraldi, Pascal; Zhao, Zhizhuang Joe; Filloux, Chantal; Fischer, Edmond H.; Obberghen, Emmanuel Van

doi:10.1073/pnas.91.11.5002

Cited by 46 publications

(18 citation statements)

References 48 publications

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“…Another possibility is that Nef-induced Erk activation may affect dephosphorylation of active Stat3 by SHP2 or other protein-tyrosine phosphatases. Erk1 has been shown to phosphorylate SHP2 and inhibit its activity in vitro, consistent with this possibility (46).…”

supporting

confidence: 61%

HIV-1 Nef Promotes Survival of TF-1 Macrophages by Inducing Bcl-X Expression in an Extracellular Signal-regulated Kinase-dependent Manner

Choi

Smithgall

2004

Journal of Biological Chemistry

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supporting

confidence: 61%

HIV-1 Nef Promotes Survival of TF-1 Macrophages by Inducing Bcl-X Expression in an Extracellular Signal-regulated Kinase-dependent Manner

Choi

Smithgall

2004

Journal of Biological Chemistry

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“…The steady state level of receptor tyrosine phosphorylation probably reflects a dynamic balance of receptor kinase activity and PTP activity. Perhaps Syp activity is inhibited immediately following receptor activation, by a mechanism such as threonine phosphorylation mediated by activated MAP kinase (44). Alternatively, tyrosine phosphorylation of Syp may act as a timer, so that Syp first dephosphorylates itself (43) and only then begins to dephosphorylate other proteins.…”

Section: Discussionmentioning

confidence: 99%

Identification of a Putative Syp Substrate, the PDGFβ Receptor

Klinghoffer

Kazlauskas

1995

Journal of Biological Chemistry

145

112

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Because the protein-tyrosine phosphatase (PTP) Syp associates with the tyrosine-phosphorylated platelet-derived growth factor ␤ receptor (␤PDGFR), the ␤PDGFR is a likely Syp substrate. We tested this hypothesis by determining whether recombinant Syp (rSyp) and a control PTP, recombinant PTP1B (rPTP1B), were able to dephosphorylate the ␤PDGFR. The ␤PDGFR was phosphorylated at multiple tyrosine residues in an in vitro kinase assay and then incubated with increasing concentrations of rSyp or rPTP1B. While the receptor was nearly completely dephosphorylated by high concentrations of rPTP1B, receptor dephosphorylation by rSyp plateaued at approximately 50%. Two-dimensional phosphopeptide maps of the ␤PDGFR demonstrated that rSyp displayed a clear preference for certain receptor phosphorylation sites; the most efficiently dephosphorylated sites were phosphotyrosines (Tyr(P))-771 and -751, followed by Tyr(P)-740, while Tyr(P)-1021 and Tyr(P)-1009 were very poor substrates. In contrast, rPTP1B displayed no selectivity for the various ␤PDGFR tyrosine phosphorylation sites and dephosphorylated all of them with comparable efficiency. A Syp construct that lacked the SH2 domains was still able to discriminate between the various receptor phosphorylation sites, although less effectively than full-length Syp.These in vitro studies predicted that Syp can dephosphorylate the receptor in vivo. Indeed, we found that a ␤PDGFR mutant (F1009) that associates poorly with Syp, had a much slower in vivo rate of receptor dephosphorylation than the wild type receptor. In addition, the GTPase-activating protein of Ras (GAP) and phosphatidylinositol 3-kinase were less stably associated with the wild type ␤PDGFR than with the F1009 receptor. These findings are consistent with the in vitro experiments showing that Syp prefers to dephosphorylate sites on the ␤PDGFR, that are important for binding phosphatidylinositol 3-kinase (Tyr(P)-740 and Tyr(P)-751) and GAP (Tyr(P)-771). These studies reveal that Syp is a substrate-selective PTP and that both the catalytic domain and the SH2 domains contribute to Syp's ability to choose substrates. Furthermore, it appears that Syp plays a role in PDGF-dependent intracellular signal relay by selectively dephosphorylating the ␤PDGFR and thereby regulating the binding of a distinct group of receptor-associated signal relay enzymes.Tyrosine phosphorylation modulates the activity of many enzymes involved in regulation of a wide variety of cellular events and is a reversible process governed by the opposing effects of protein-tyrosine kinases and protein-tyrosine phosphatases (PTPs) 1 (1-3). In addition to a conserved catalytic domain, most PTPs also contain highly variable noncatalytic sequences, which can regulate the activity and/or subcellular location of the PTP (1, 3). The initially purified PTPs failed to show a high degree of substrate specificity (4), and this led to the hypothesis that subcellular targeting is the primary determinant in selection of a substrate. More recent evidence indicates that an i...

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“…Moreover, we found that MAP kinase activity in these Tg mice was not impaired, and the growth rate was normal, although insulin could not activate further the enzyme activity. Some compensatory mechanisms to regulate MAP kinase cascade in our Tg mice might have occurred (39).…”

Section: Discussionmentioning

confidence: 99%

Expression of a Dominant Negative SHP-2 in Transgenic Mice Induces Insulin Resistance

Maegawa

Hasegawa

Sugai

et al. 1999

Journal of Biological Chemistry

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To elucidate the roles of SHP-2, we generated transgenic (Tg) mice expressing a dominant negative mutant lacking protein tyrosine phosphatase domain (⌬PTP). On examining two lines of Tg mice identified by Southern blot, the transgene product was expressed in skeletal muscle, liver, and adipose tissues, and insulin-induced association of insulin receptor substrate 1 with endogenous SHP-2 was inhibited, confirming that ⌬PTP has a dominant negative property. The intraperitoneal glucose loading test demonstrated an increase in blood glucose levels in Tg mice. Plasma insulin levels in Tg mice after 4 h fasting were 3 times greater with comparable blood glucose levels. To estimate insulin sensitivity by a constant glucose, insulin, and somatostatin infusion, steady state blood glucose levels were higher, suggesting the presence of insulin resistance. Furthermore, we observed the impairment of insulin-stimulated glucose uptake in muscle and adipocytes in the presence of physiological concentrations of insulin. Moreover, tyrosine phosphorylation of insulin receptor substrate-1 and stimulation of phosphatidylinositol 3-kinase and Akt kinase activities by insulin were attenuated in muscle and liver. These results indicate that the inhibition of endogenous SHP-2 function by the overexpression of a dominant negative mutant may lead to impaired insulin sensitivity of glucose metabolism, and thus SHP-2 may function to modulate insulin signaling in target tissues. SHP-2 (also referred to as PTP1D, PTP2C, SHPTP2, or SYP)is a ubiquitously expressed protein-tyrosine phosphatase (PTPase) 1 containing a single PTPase domain and two adjacent Src homology (SH) 2 domains near its N terminus which specifically associate with a variety of tyrosine-phosphorylated proteins upon growth factor stimulation (1-5). SHP-2 is the mammalian homologue of Drosophila Corkscrew, whose gene product potentiates the Drosophila homologue of mammalian c-raf to positively transmit signals downstream of the Torso receptor tyrosine kinase (6). Furthermore, SHP-2 has been reported to play an important role in mesodermal induction in oocyte by regulation of mitogen-activated protein (MAP) kinase activity (7).Regarding the roles of SHP-2 in tyrosine kinase signaling, several lines of evidence indicate that SHP-2 acts as a positive mediator in growth factor signaling such as that by plateletderived growth factor and epidermal growth factor (4,5,8,9). After stimulation by these ligands, SHP-2 is tyrosine-phosphorylated and bound to Grb2-SOS complex, resulting in activation of p21 ras and MAP kinase cascade. On the other hand, in the case of insulin signaling, SHP-2 is not tyrosine-phosphorylated in response to insulin stimulation. However, insulin induces the association of IRS-1 with SHP-2 (10, 11), and the expression of either a catalytically inactive mutant SHP-2 (Cys/Ser) or a deletion mutant lacking PTPase domain in Chinese hamster ovary cells overexpressing insulin receptors (CHO-IR) results in the attenuation of the insulin-stimulated MAP kinase activity, ...

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Protein-tyrosine-phosphatase 2C is phosphorylated and inhibited by 44-kDa mitogen-activated protein kinase.

Cited by 46 publications

References 48 publications

HIV-1 Nef Promotes Survival of TF-1 Macrophages by Inducing Bcl-X Expression in an Extracellular Signal-regulated Kinase-dependent Manner

HIV-1 Nef Promotes Survival of TF-1 Macrophages by Inducing Bcl-X Expression in an Extracellular Signal-regulated Kinase-dependent Manner

Identification of a Putative Syp Substrate, the PDGFβ Receptor

Expression of a Dominant Negative SHP-2 in Transgenic Mice Induces Insulin Resistance

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