scholarly journals PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase

Blood ◽  
2006 ◽  
Vol 109 (3) ◽  
pp. 862-867 ◽  
Author(s):  
Rebecca J. Chan ◽  
Gen-Sheng Feng
Keyword(s):  
Tumor Suppressor Genes ◽  
Molecular Mechanisms ◽  
Cell Transformation ◽  
Tyrosine Phosphatase ◽  
Research Field ◽  
Sh2 Domains ◽  
Src Homology 2 ◽  
Src Homology ◽  
Identification And Characterization

Abstract Elucidation of the molecular mechanisms underlying carcinogenesis has benefited tremendously from the identification and characterization of oncogenes and tumor suppressor genes. One new advance in this field is the identification of PTPN11 as the first proto-oncogene that encodes a cytoplasmic tyrosine phosphatase with 2 Src-homology 2 (SH2) domains (Shp2). This tyrosine phosphatase was previously shown to play an essential role in normal hematopoiesis. More recently, somatic missense PTPN11 gain-of-function mutations have been detected in leukemias and rarely in solid tumors, and have been found to induce aberrant hyperactivation of the Ras-Erk pathway. This progress represents another milestone in the leukemia/cancer research field and provides a fresh view on the molecular mechanisms underlying cell transformation.

scholarly journals Inhibition of SHP2 ameliorates psoriasis by decreasing TLR7 endosome localization

2020 ◽  
Author(s):  
Yuyu Zhu ◽  
Fenli Shao ◽  
Wei Yan ◽  
Qiang Xu ◽  
Yang Sun
Keyword(s):  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Tyrosine Phosphatase ◽  
Skin Inflammation ◽  
Peripheral Blood Mononuclear ◽  
Genetic Ablation ◽  
Src Homology 2 ◽  
Promising Therapeutic Approach ◽  
Src Homology ◽  
Src Homology 2 Domain

Psoriasis is a complex chronic inflammatory skin disease with unclear molecular mechanisms. Here, we identify Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) as a novel accelerator of psoriasis development. Both genetic ablation of SHP2 in macrophages and pharmacological inhibition of SHP2 prevents the development of psoriasis-like skin inflammation in an imiquimod-induced murine model of psoriasis. Mechanistically, SHP2 promotes the trafficking of Toll-like receptor 7 (TLR7) from Golgi to endosome through its interaction with and dephosphorylation of TLR7 at Tyr1024, which promotes the ubiquitination of TLR7 and psoriasis-like skin inflammation. Importantly, SHP2 allosteric inhibitor SHP099 reduces the expression of pro-inflammatory cytokines in peripheral blood mononuclear cells from human patients with psoriasis. Collectively, our findings identify SHP2 as a novel regulator of psoriasis and suggest that SHP2 inhibition may be a promising therapeutic approach for psoriatic patients.

scholarly journals SHP-2-Induced Activation of c-Myc Is Involved in PDGF-B-Regulated Cell Proliferation and Angiogenesis in RMECs

2020 ◽  
Vol 11 ◽  
Author(s):  
Jun Ma ◽  
Wenyi Tang ◽  
Ruiping Gu ◽  
Fangyuan Hu ◽  
Lei Zhang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Molecular Mechanisms ◽  
Tyrosine Phosphatase ◽  
Tube Formation ◽  
Proliferative Retinopathy ◽  
Cell Counting ◽  
Brdu Incorporation ◽  
Src Homology 2 ◽  
Src Homology ◽  
Src Homology 2 Domain

Background: Aberrant neovascularization resulting from inappropriate angiogenic signaling is closely related to many diseases, such as cancer, cardiovascular disease, and proliferative retinopathy. Although some factors involved in regulating pathogenic angiogenesis have been identified, the molecular mechanisms of proliferative retinopathy remain largely unknown. In the present study, we determined the role of platelet-derived growth factor-B (PDGF-B), one of the HIF-1-responsive gene products, in cell proliferation and angiogenesis in retinal microvascular endothelial cells (RMECs) and explored its regulatory mechanism.Methods: Cell counting kit-8 (CCK-8), bromodeoxyuridine (BrdU) incorporation, tube formation, cell migration, and Western blot assays were used in our study.Results: Our results showed that PDGF-B promoted cell proliferation and angiogenesis by increasing the activity of Src homology 2 domain-containing tyrosine phosphatase 2 (SHP-2) in RMECs, which was attenuated by the inhibition of PDGF receptor (PDGFR) or SHP-2 knockdown. Moreover, activation of c-Myc was involved in the processes of PDGF-B/SHP-2-driven cell proliferation in RMECs. The promoting effects of PDGF-B/SHP-2 on c-Myc expression were mediated by the Erk pathway.Conclusion: These results indicate that PDGF-B facilitates cell proliferation and angiogenesis, at least in part, via the SHP-2/Erk/c-Myc pathway in RMECs, implying new potential treatment candidates for retinal microangiopathy.

scholarly journals The Effect of Transient Global Ischemia on the Interaction of Src and Fyn with the N-Methyl-d-Aspartate Receptor and Postsynaptic Densities: Possible Involvement of Src Homology 2 Domains

1999 ◽  
Vol 19 (8) ◽  
pp. 880-888 ◽  
Author(s):  
Norio Takagi ◽  
Herman H. Cheung ◽  
Nankie Bissoon ◽  
Lucy Teves ◽  
M. Christopher Wallace ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Tyrosine Phosphorylation ◽  
Tyrosine Phosphatase ◽  
Sh2 Domain ◽  
Signaling Proteins ◽  
Glutathione S Transferase ◽  
Nmda Receptor Subunits ◽  
Sh2 Domains ◽  
Src Homology 2 ◽  
Src Homology

Transient ischemia increases tyrosine phosphorylation of N-methyl-d-aspartate (NMDA) receptor subunits NR2A and NR2B in the rat hippocampus. The authors investigated the effects of this increase on the ability of the receptor subunits to bind to the Src homology 2 (SH2) domains of Src and Fyn expressed as glutathione-S-transferase–SH2 fusion proteins. The NR2A and NR2B bound to each of the SH2 domains and binding was increased approximately twofold after ischemia and reperfusion. Binding was prevented by prior incubation of hippocampal homogenates with a protein tyrosine phosphatase or by a competing peptide for the Src SH2 domain. Ischemia induced a marked increase in the tyrosine phosphorylation of several proteins in the postsynaptic density (PSD), including NR2A and NR2B, but had no effect on the amounts of individual NMDA receptor subunits in the PSD. The level of Src and Fyn in PSDs, but not in other subcellular fractions, was increased after ischemia. The ischemia-induced increase in the interaction of NR2A and NR2B with the SH2 domains of Src and Fyn suggests a possible mechanism for the recruitment of signaling proteins to the PSD and may contribute to altered signal transduction in the postischemic hippocampus.

Role of SH-PTP2, a protein-tyrosine phosphatase with Src homology 2 domains, in insulin-stimulated Ras activation

1994 ◽  
Vol 14 (10) ◽  
pp. 6674-6682
Author(s):  
T Noguchi ◽  
T Matozaki ◽  
K Horita ◽  
Y Fujioka ◽  
M Kasuga
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Chinese Hamster Ovary Cells ◽  
Tyrosine Phosphatase ◽  
Chinese Hamster ◽  
Protein Tyrosine ◽  
Sh2 Domains ◽  
Src Homology 2 ◽  
Ras Activation ◽  
Src Homology ◽  
Upstream Element

SH-PTP2 is a nontransmembrane human protein-tyrosine phosphatase that contains two Src homology 2 (SH2) domains and binds to insulin receptor substrate 1 (IRS-1) via these domains in response to insulin. The expression of a catalytically inactive mutant of SH-PTP2 (containing the mutation Cys-459-->Ser) in Chinese hamster ovary cells that overexpress human insulin receptors (CHO-IR cells) markedly attenuated insulin-stimulated Ras activation. Expression of mutant SH-PTP2 also inhibited MAP kinase activation in response to insulin but not in response to 12-O-tetradecanoyl phorbol-13-acetate. In contrast, the insulin-induced association of phosphoinositide 3-kinase activity with IRS-1 was not affected by the expression of inactive SH-PTP2. Furthermore, the expression of mutant SH-PTP2 had no effect on the binding of Grb2 to IRS-1, on the tyrosine phosphorylation of Shc, or on the formation of the complex between Shc and Grb2 in response to insulin. However, the amount of SH-PTP2 bound to IRS-1 in insulin-treated CHO-IR cells expressing mutant SH-PTP2 was greater than that observed in CHO-IR cells overexpressing wild-type SH-PTP2. Recombinant SH-PTP2 specifically dephosphorylated a synthetic phosphopeptide corresponding to the sequence surrounding Tyr-1172 of IRS-1, a putative binding site for SH-PTP2. Additionally, phenylarsine oxide, an inhibitor of protein-tyrosine phosphatases, inactivated SH-PTP2 in vitro and increased the insulin-induced association of SH-PTP2 with IRS-1. These results suggest that SH-PTP2 may regulate an upstream element necessary for Ras activation in response to insulin and that this upstream element may be required for the Grb2- or Shc-dependent pathway. Furthermore, these results are consistent with the notion that SH-PTP2 may bind to IRS-1 through its SH2 domains in response to insulin and dephosphorylate the phosphotyrosine residue to which it binds, thereby regulating its association with IRS-1.

scholarly journals Role of SH-PTP2, a protein-tyrosine phosphatase with Src homology 2 domains, in insulin-stimulated Ras activation.

1994 ◽  
Vol 14 (10) ◽  
pp. 6674-6682 ◽  
Author(s):  
T Noguchi ◽  
T Matozaki ◽  
K Horita ◽  
Y Fujioka ◽  
M Kasuga
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Chinese Hamster Ovary Cells ◽  
Tyrosine Phosphatase ◽  
Chinese Hamster ◽  
Protein Tyrosine ◽  
Sh2 Domains ◽  
Src Homology 2 ◽  
Ras Activation ◽  
Src Homology ◽  
Upstream Element

SH-PTP2 is a nontransmembrane human protein-tyrosine phosphatase that contains two Src homology 2 (SH2) domains and binds to insulin receptor substrate 1 (IRS-1) via these domains in response to insulin. The expression of a catalytically inactive mutant of SH-PTP2 (containing the mutation Cys-459-->Ser) in Chinese hamster ovary cells that overexpress human insulin receptors (CHO-IR cells) markedly attenuated insulin-stimulated Ras activation. Expression of mutant SH-PTP2 also inhibited MAP kinase activation in response to insulin but not in response to 12-O-tetradecanoyl phorbol-13-acetate. In contrast, the insulin-induced association of phosphoinositide 3-kinase activity with IRS-1 was not affected by the expression of inactive SH-PTP2. Furthermore, the expression of mutant SH-PTP2 had no effect on the binding of Grb2 to IRS-1, on the tyrosine phosphorylation of Shc, or on the formation of the complex between Shc and Grb2 in response to insulin. However, the amount of SH-PTP2 bound to IRS-1 in insulin-treated CHO-IR cells expressing mutant SH-PTP2 was greater than that observed in CHO-IR cells overexpressing wild-type SH-PTP2. Recombinant SH-PTP2 specifically dephosphorylated a synthetic phosphopeptide corresponding to the sequence surrounding Tyr-1172 of IRS-1, a putative binding site for SH-PTP2. Additionally, phenylarsine oxide, an inhibitor of protein-tyrosine phosphatases, inactivated SH-PTP2 in vitro and increased the insulin-induced association of SH-PTP2 with IRS-1. These results suggest that SH-PTP2 may regulate an upstream element necessary for Ras activation in response to insulin and that this upstream element may be required for the Grb2- or Shc-dependent pathway. Furthermore, these results are consistent with the notion that SH-PTP2 may bind to IRS-1 through its SH2 domains in response to insulin and dephosphorylate the phosphotyrosine residue to which it binds, thereby regulating its association with IRS-1.

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