Role of SHP-2 Tyrosine Phosphatase in the DNA Damage-induced Cell Death Response

Yuan, Liangping; Yu, Wen Mei; Yuan, Zhi-Min; Haudenschild, Christian C.; Qu, Cheng Kui

doi:10.1074/jbc.m211327200

Cited by 38 publications

(40 citation statements)

References 66 publications

(38 reference statements)

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“…This result suggests that the deleted sequences encoding the Nterminal region of SHP-2 are required for stabilization of either its mRNA transcripts or protein. Remarkably, the expression level of the truncated form of SHP-2 in the mutant hematopoietic cells is much lower than that detected in SHP-2 À/À ES cells or embryonic fibroblast cells (Qu et al, 1997;Yuan et al, 2003).…”

Section: Immortalization Of Shp-2 Mutant Hematopoietic Cellsmentioning

confidence: 72%

Catalytic-dependent and -independent roles of SHP-2 tyrosine phosphatase in interleukin-3 signaling

Hawley

et al. 2003

Oncogene

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Section: Immortalization Of Shp-2 Mutant Hematopoietic Cellsmentioning

confidence: 72%

Catalytic-dependent and -independent roles of SHP-2 tyrosine phosphatase in interleukin-3 signaling

Hawley

et al. 2003

Oncogene

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“…As SHP-2 regulates ERK activation in only a small fraction of activated T cells, but the majority of T cells undergo SHP-2-mediated apoptosis, the ERK pathway is not the death-inducing pathway which has also been suggested in experiments using bulk cultures of the pro-B cell line Ba/F3 [46]. In SHP-2-deficient fibroblasts an apoptosis-enhancing role of SHP-2 WT was described after cisplatin-induced cell death [47], which could mimic our intrinsic apoptosis-prone effect that we have observed in T lymphocytes transduced with full-length SHP-2 cDNA.…”

Section: Discussionmentioning

confidence: 91%

The tyrosine phosphatase SHP‐2 regulates differentiation and apoptosis of individual primary T lymphocytes

Hoff

Brunner‐Weinzierl

2007

Eur J Immunol

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Although phosphatases are key players of intracellular processes, not much is known about the phosphatase SHP-2 during T cell differentiation. Here we show that ectopic over-expression of SHP-2 in primary T helper cells directly reduced the frequency of individual lymphocytes expressing pro-inflammatory cytokines after antigen-specific stimulation by a mechanism impairing activation of protein kinase C. In addition we demonstrate that SHP-2 mediates enhanced migration upon CXCR4 signaling in a G-protein-dependent manner. Most strikingly, SHP-2 mediated a dramatic increase in apoptosis by highly enhanced activation of caspases. Co-immunoprecipitations of SHP-2 and c-Cbl from primary T helper cells demonstrated that SHP-2 strongly interacts with the ubiquitin ligase c-Cbl, indicating that c-Cbl could mediate the negative signals of SHP-2. Our results show that SHP-2 signal transduction regulates central checkpoints of T cell differentiation by the activation of distinct signaling cascades.

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“…The roles of SHP-2 in mediating cellular growth and survival by activating Ras-MAPK and Akt signaling, thereby protecting cells from apoptosis, are well studied. In contrast, some studies suggest that SHP-2 is involved in mediating apoptosis in response to DNA damage or deprivation of growth factors (19,20). However, the downstream targets of SHP-2 in mediating cell survival or apoptosis are not well characterized.…”

Section: Discussionmentioning

confidence: 98%

“…2C). Because the response of these cells to EGCG was in sharp contrast to their response to DNA damage (20), we treated the cells with two DNA-damaging agents, camptothecin and cisplatin, and examined them for p21 expression. As shown in Fig.…”

Section: Shp-2 Negatively Regulates Apoptosis Induced By Egcgmentioning

confidence: 99%

SHP-2 tyrosine phosphatase inhibits p73-dependent apoptosis and expression of a subset of p53 target genes induced by EGCG

Amin¹,

Thakur²,

Paul³

et al. 2007

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

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Green tea polyphenol, epigallocatechin-3-gallate (EGCG) differentially regulates the cellular growth of cancer cells in a p53-dependent manner through apoptosis and/or cell cycle arrest. In an effort to further elucidate the mechanism of differential growth regulation by EGCG, we have investigated the role of the tyrosine phosphatase, SHP-2. Comparing the responses of mouse embryonic fibroblasts (MEFs), expressing either WT or functionally inactive/truncated SHP-2, we find that inactivation of SHP-2 remarkably sensitizes cells to EGCG-mediated killing. MEFs lacking functional SHP-2 undergo massive apoptosis upon treatment with EGCG. By comparing gene expression profiles, we have identified a set of transcriptional targets of p53 that are differentially modulated in cells undergoing apoptosis. Western blot and real-time PCR analyses of a select group of genes further confirm that the expression is SHP-2-dependent. Similar observations were made in MEFs lacking p53, confirming that the expression of these ''p53 target genes'' is p53-independent. In addition, EGCG treatment induced the expression of p73 mRNA and protein in both cell types, but not p63. Inactivation of p73 in cells expressing nonfunctional SHP-2 markedly inhibited apoptosis and p53 target gene expression. Although phosphorylation of JNK is differentially regulated by SHP2, it was found to be dispensable for EGCG-induced apoptosis and p53 target gene expression. Our results have identified SHP-2 as a negative regulator of EGCG-inducedapoptosis and have identified a subset of p53 target genes whose expression is paradoxically not mediated by p53 but by one of its family members, p73.green tea ͉ MAPK pathway ͉ mouse embryonic fibroblasts ͉ transcriptional activation

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Role of SHP-2 Tyrosine Phosphatase in the DNA Damage-induced Cell Death Response

Cited by 38 publications

References 66 publications

Catalytic-dependent and -independent roles of SHP-2 tyrosine phosphatase in interleukin-3 signaling

Catalytic-dependent and -independent roles of SHP-2 tyrosine phosphatase in interleukin-3 signaling

The tyrosine phosphatase SHP‐2 regulates differentiation and apoptosis of individual primary T lymphocytes

SHP-2 tyrosine phosphatase inhibits p73-dependent apoptosis and expression of a subset of p53 target genes induced by EGCG

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