SHP-1 Regulates Lck-induced Phosphatidylinositol 3-Kinase Phosphorylation and Activity

Cuevas, Bruce D.; Lu, Yiling; Watt, Stephen A.; Kumar, Rakesh; Zhang, Jinyi; Siminovitch, Katherine A.; Mills, Gordon B.

doi:10.1074/jbc.274.39.27583

Cited by 141 publications

(135 citation statements)

References 44 publications

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“…In contrast, this transient increase was absent in SHP-1-overexpressing cells and p85 immunodetection was, in fact, completely lost by TSA-treatment for 48 h. Stable overexpression of SHP-1 during TSA treatment may induce an actual downregulation of total cellular p85 protein rather than a diminished phosphorylation of p85, which was proposed to account for the regulation of p85 activity by transient SHP-1 expression. 5,11 The reduction in phosphorylation of Akt observed in TSA-treated SHP-1 transfectants was not observed in SHP-1-C455S transfectants, concurring with the observation that SHP-1, but not the catalytic inactive mutant, can negatively regulate p56 Lckinduced phospho-PI3K activity and phosphorylation of Akt (Figure 1). 11 Treatment with the tyrosine phosphatase inhibitor vanadate inhibits apoptosis by activation of PI3K/Akt, and phosphorylation of Bad.…”

supporting

confidence: 86%

SHP-1 sensitizes MCF-7 cells to trichostatin A-induced apoptosis by modulating PI3K-dependent events

Banville

et al. 2003

Cell Death Differ

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supporting

confidence: 86%

SHP-1 sensitizes MCF-7 cells to trichostatin A-induced apoptosis by modulating PI3K-dependent events

Banville

et al. 2003

Cell Death Differ

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“…Akt activation has been shown to depend on phosphorylation of a speci®c serine (Ser473) (Alessi et al, 1996). Evaluation of Akt Ser473 phosphorylation provides a surrogate assay for PI3K activity in intact cells (Cuevas et al, 1999), and is much easier to perform than direct lipid kinase activity analysis. To investigate SHP-2 regulation of EGF induced Akt phosphorylation, we ®rst introduced wildtype SHP-2 and its variants, each mutated at one of its three domains, into U87MG cells [R32E in the Nterminal SH2 domain and R138E in the C-terminal SH2 domain render the two SH2 domains incapable of Figure 1 EGF stimulation as well as DEGFR expression enhances the co-immunoprecipitation of the p85 subunit of PI3K with SHP-2.…”

Section: Resultsmentioning

confidence: 99%

“…Growth factorinduced physical association of SHP-2 and PI3K is supported by the observation that a large amount of PI3K activities were detected in anti-SHP-2 immunoprecipitates after EGF or IGF-I stimulation in human skin ®broblasts (Takahashi et al, 1999). SHP-1 has been shown to directly bind to p85, and the inducible binding has been suggested to be responsible for its negative regulation of Lck-induced PI3K activation (Cuevas et al, 1999). However, the association of SHP-2 and p85 appears to occur in a much larger complex with Gab1 (Holgado-Madruga et al, 1996), Cb1 (Hakak et al, 2000;Fixman et al, 1997), as well as a 97-100KD protein (Gesbert et al, 1998;Craddock et al, 1997;Carlberg and Rohrschneider, 1997), possibly Gab2 (Gu et al, 1998) and/or SIRP (Kharitonenkov et al, 1997).…”

Section: Shp-2 Mediates Pi3k Activationmentioning

confidence: 86%

The tyrosine phosphatase SHP-2 is required for mediating phosphatidylinositol 3-kinase/Akt activation by growth factors

et al. 2001

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SHP-2 is a ubiquitously expressed non-transmembrane tyrosine phosphatase with two SH2 domains. Multiple reverse-genetic studies have indicated that SHP-2 is a required component for organ and animal development. SHP-2 wild-type and homozygous mutant mouse ®bro-blast cells in which the N-terminal SH2 domain was target-deleted were used to examine the function of SHP-2 in regulating Phosphatidylinositol 3-Kinase (PI3K) activation by growth factors. In addition, SHP-2 and various mutants were introduced into human glioblastoma cells as well as SHP-2 7/7 mouse ®bro-blasts. We found that EGF stimulation and EGFR oncoprotein (DEGFR) expression independently induced the co-immunoprecipitation of the p85 subunit of PI3K with SHP-2. Targeted deletion of the N-terminal SH2 domain of SHP-2 severely impaired PDGF-and IGFinduced Akt phosphorylation. Ectopic expression of SHP-2 in U87MG gliobastoma cells elevated EGFinduced Akt phosphorylation, and the e ect was abolished by mutation of its N-terminal SH2 domain. Likewise, the reconstitution of SHP-2 expression in the SHP-2 7/7 cells enhanced Akt phosphorylation induced by EGF while rescuing that induced by PDGF and IGF. Further lipid kinase activity assays con®rmed that SHP-2 modulation of Akt phosphorylation correlated with its regulation of PI3K activation. Based on these results, we conclude that SHP-2 is required for mediating PI3K/Akt activation, and the N-terminal SH2 domain is critically important for a`positive' role of SHP-2 in regulating PI3K pathway activation. Oncogene (2001) 20, 6018 ± 6025.

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“…Many signaling pathways induce PI3K activation, although the level of PI3K activation and the downstream effector molecules vary depending on the signaling pathway. TCR cross-linking/ligation can activate PI3K, in part through Lck (39) and Gab2 adapter proteins (40). CD28 can directly activate PI3K through recruitment of p85 subunit (41).…”

Section: Discussionmentioning

confidence: 99%

Antigen-Independent Induction of Tim-3 Expression on Human T Cells by the Common γ-Chain Cytokines IL-2, IL-7, IL-15, and IL-21 Is Associated with Proliferation and Is Dependent on the Phosphoinositide 3-Kinase Pathway

Mujib

Jones

et al. 2012

The Journal of Immunology

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T cell Ig mucin domain-containing molecule 3 (Tim-3) is a glycoprotein found on the surface of a subset of CD8+ and Th1 CD4+ T cells. Elevated expression of Tim-3 on virus-specific T cells during chronic viral infections, such as HIV-1, hepatitis B virus, and hepatitis C virus, positively correlates with viral load. Tim-3+ cytotoxic T cells are dysfunctional and are unable to secrete effector cytokines, such as IFN-γ and TNF-α. In this study, we examined potential inducers of Tim-3 on primary human T cells. Direct HIV-1 infection of CD4+ T cells, or LPS, found to be elevated in HIV-1 infection, did not induce Tim-3 on T cells. Tim-3 was induced by the common γ-chain (γc) cytokines IL-2, IL-7, IL-15, and IL-21 but not IL-4, in an Ag-independent manner and was upregulated on primary T cells in response to TCR/CD28 costimulation, as well as γc cytokine stimulation with successive divisions. γc cytokine-induced Tim-3 was found on naive, effector, and memory subsets of T cells. Tim-3+ primary T cells were more prone to apoptosis, particularly upon treatment with galectin-9, a Tim-3 ligand, after cytokine withdrawal. The upregulation of Tim-3 could be blocked by the addition of a PI3K inhibitor, LY 294002. Thus, Tim-3 can be induced via TCR/CD28 costimulation and/or γc cytokines, likely through the PI3K pathway.

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SHP-1 Regulates Lck-induced Phosphatidylinositol 3-Kinase Phosphorylation and Activity

Abstract: Ligation of the T cell antigen receptor (TCR) activates

Cited by 141 publications

References 44 publications

SHP-1 sensitizes MCF-7 cells to trichostatin A-induced apoptosis by modulating PI3K-dependent events

SHP-1 sensitizes MCF-7 cells to trichostatin A-induced apoptosis by modulating PI3K-dependent events

The tyrosine phosphatase SHP-2 is required for mediating phosphatidylinositol 3-kinase/Akt activation by growth factors

Antigen-Independent Induction of Tim-3 Expression on Human T Cells by the Common γ-Chain Cytokines IL-2, IL-7, IL-15, and IL-21 Is Associated with Proliferation and Is Dependent on the Phosphoinositide 3-Kinase Pathway

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