SHP‐1 dephosphorylates 3BP2 and potentially downregulates 3BP2‐mediated T cell antigen receptor signaling

Yu, Zhenbao; Maoui, Meryem; Zhao, Zhizhuang Joe; Li, Yang; Shen, Shi-Hsiang

doi:10.1111/j.1742-4658.2006.05233.x

Cited by 13 publications

(14 citation statements)

References 44 publications

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“…In this study, we disclosed that SHP-1 is a potential tumor suppressor, and a direct target of regorafenib for anti-HCC. Previously, SHP-1 was found to be responsible for several immune responses in hematopoietic cells, such as trapping by inhibitory ITAM signaling to form inhibisome clusters (9), negative regulation of T-cell receptor engagement by inactivation of Lck (10), and downregulation of T-cell antigen receptor signaling by direct dephosphorylation of 3BP2 (11).…”

Section: Discussionmentioning

confidence: 99%

STAT3 Mediates Regorafenib-Induced Apoptosis in Hepatocellular Carcinoma

Tai

Chu

Shiau³

et al. 2014

Clinical Cancer Research

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Purpose: Here, we aim to investigate the molecular mechanism of regorafenib and verify the potential druggable target for the treatment of hepatocellular carcinoma (HCC).Experimental Design: HCC cell lines (PLC5, HepG2, Hep3B, SK-Hep1, and HA59T) were used to investigate the in vitro effect of regorafenib. Phosphatase activity was analyzed in HCC cells and purified SHP-1 proteins. PLC5-bearing mice were used to test the therapeutic efficiency of 20 and 40 mg/kg/d treatment with regorafenib (n ! 8 mice). The clinical relevance of STAT3 signaling was investigated with 142 tumor samples from different patients with HCC. Descriptive statistical analysis was used to compare the baseline characteristics of patients and the expression of p-STAT3.Results: Regorafenib inhibited STAT3-related signaling in a dose-dependent manner and was a more potent inhibitor of STAT3 than sorafenib. Regorafenib increased SHP-1 phosphatase activity in purified SHP-1 protein directly. N-SH2 domain deletion and D61A mutants mimicking open-form SHP-1 partially abolished regorafenib-induced STAT3 inhibition and apoptosis. Importantly, a higher level of expression of STAT3 was found in patients with advanced clinical stages (P ¼ 0.009) and poorly differentiated tumors (P ¼ 0.035).Conclusions: Regorafenib induced significant tumor inhibition by relieving the autoinhibited N-SH2 domain of SHP-1 directly and inhibiting p-STAT3 signals. STAT3 may be suitable as a prognostic marker of HCC development, and may be a druggable target for HCC-targeted therapy using regorafenib. Clin Cancer Res; 20(22); 5768-76. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 99%

STAT3 Mediates Regorafenib-Induced Apoptosis in Hepatocellular Carcinoma

Tai

Chu

Shiau³

et al. 2014

Clinical Cancer Research

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“…Phosphorylation of Ser 225 and Ser 277 are required for 14-3-3 binding, and a SH3BP2 protein lacking these serines was shown to have increased activity in Jurkat TAg cells [40]. In T cells, SH3BP2 is phosphorylated on tyrosine 448 in response to T cell receptor stimulation and this phosphorylation is required for T cell signaling as indicated by NFAT activiation [50]. Further, phosphorylation of SHP1 phosphatase causes recruitment and dephosphorylation of SH3BP2 and termination of T cell signaling [50].…”

Section: Sh3bp2 Function In Immune Cellsmentioning

confidence: 99%

“…In T cells, SH3BP2 is phosphorylated on tyrosine 448 in response to T cell receptor stimulation and this phosphorylation is required for T cell signaling as indicated by NFAT activiation [50]. Further, phosphorylation of SHP1 phosphatase causes recruitment and dephosphorylation of SH3BP2 and termination of T cell signaling [50]. SH3BP2 phosphorylation is also induced by CD244 ligation and tyrosine 337 phosphorylation of CD244 regulates its interaction with SH3BP2 in NK cells [51].…”

Section: Sh3bp2 Function In Immune Cellsmentioning

confidence: 99%

The role of SH3BP2 in the pathophysiology of cherubism

Reichenberger

Levine

Olsen

et al. 2012

Orphanet Journal of Rare Diseases

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Cherubism is a rare bone dysplasia that is characterized by symmetrical bone resorption limited to the jaws. Bone lesions are filled with soft fibrous giant cell-rich tissue that can expand and cause severe facial deformity. The disorder typically begins in children at ages of 2-5 years and the bone resorption and facial swelling continues until puberty; in most cases the lesions regress spontaneously thereafter. Most patients with cherubism have germline mutations in the gene encoding SH3BP2, an adapter protein involved in adaptive and innate immune response signaling. A mouse model carrying a Pro416Arg mutation in SH3BP2 develops osteopenia and expansile lytic lesions in bone and some soft tissue organs. In this review we discuss the genetics of cherubism, the biological functions of SH3BP2 and the analysis of the mouse model. The data suggest that the underlying cause for cherubism is a systemic autoinflammatory response to physiologic challenges despite the localized appearance of bone resorption and fibrous expansion to the jaws in humans.

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“…The SH2 domains of SHP-1 have recently been revealed to downregulate the activity of a number of kinases to negatively regulate signal transduction and to inhibit cell proliferation (14,16–21). Activated SHP-1 has been demonstrated to catalyze tyrosine dephosphorylation of the Janus kinases (JAKs), src and c-fms, leading to the reduction or loss of kinase activity and the inhibition of cell proliferation (14,16–19,22–26). SHP-1 has been reported to be a negative regulator of angiogenesis (27) and to be upregulated in breast cancer (28).…”

Section: Introductionmentioning

confidence: 99%

Alterations of cell cycle control proteins SHP-1/2, p16, CDK4 and cyclin D1 in radioresistant nasopharyngeal carcinoma cells

Peng

Cao

et al. 2014

Molecular Medicine Reports

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The primary treatment for nasopharyngeal carcinoma (NPC) is radiotherapy, with or without concurrent chemotherapy. However, resistance to radiotherapy is not uncommon. The aim of the present study was to establish a radioresistant NPC cell line to study the molecular mechanisms of radioresistance by measuring the expression of cell cycle control proteins src homology 2 domain-containing phosphatase (SHP)-1/2, p16, CDK4 and cyclin D1. Human nasopharyngeal carcinoma CNE-2 cells were cultured, divided into two groups (CNE-2S1 and CNE-2S2) and irradiated with a dose of 6 Gy x5 or 2 Gy x15, respectively. The cells were subcultured between doses of irradiation. The surviving sublines (CNE-2S1 and CNE-2S2 clones) were then passaged for three months and their radiosensitivity was determined. The cell cycle distribution and protein expression of SHP-1/2, p16, CDK4 and cyclin D1 in parental and progenitor cell lines were measured. Small interfering (si)RNA-mediated knockdown of SHP-1 and SHP-2 in the NPC cells was used to further examine their roles in radiosensitivity and cell cycle distribution. CNE-2S1, a radio-resistant cell line, had a significantly higher percentage of cells in S phase and a lower percentage of cells in G1 phase, enhanced expression levels of SHP-1, CDK4 and cyclin D1, and reduced expression of p16, respectively, as compared with the parent cells. Stable suppression of SHP-1 mRNA in CNE-2 cells resulted in increased radiosensitivity compared with the parental cells, a decrease in the number of cells in S phase and an increase in the expression of p16. The results suggested that the SHP-1/p16/cyclin D1/CDK4 pathway may have a role in regulating radiosensitivity and cell cycle distribution in nasopharyngeal cells.

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SHP‐1 dephosphorylates 3BP2 and potentially downregulates 3BP2‐mediated T cell antigen receptor signaling

Cited by 13 publications

References 44 publications

STAT3 Mediates Regorafenib-Induced Apoptosis in Hepatocellular Carcinoma

STAT3 Mediates Regorafenib-Induced Apoptosis in Hepatocellular Carcinoma

The role of SH3BP2 in the pathophysiology of cherubism

Alterations of cell cycle control proteins SHP-1/2, p16, CDK4 and cyclin D1 in radioresistant nasopharyngeal carcinoma cells

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