New Role for Shc in Activation of the Phosphatidylinositol 3-Kinase/Akt Pathway

Gu, Haihua; Maeda, Hiroyuki; Moon, James J.; Lord, James D.; Yoakim, Monique; Nelson, Brad H.; Neel, Benjamin G.

doi:10.1128/mcb.20.19.7109-7120.2000

Cited by 273 publications

(285 citation statements)

References 64 publications

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“…This finding is in keeping with recent data suggesting that Shc plays a role in promoting cell survival and counteracting apoptosis in response to cytokine receptors (Gu et al, 2000) and NGF receptor (Ulrich et al, 1998;Ashcroft et al, 1999) stimulation. The occurrence of apoptosis in our experimental system can be explained by several hypotheses: (1) Shc might transduce possible TRK-T3 anti-apoptotic signals; (2) signalling through tyrosine 317 of Shc could counteract a possible pro-apoptotic pathway induced by TRK-T3; (3) a pro-apoptotic signal might be the consequence of cell stress due to incorrectly transduced TRK-T3 signalling.…”

Section: Discussionsupporting

confidence: 92%

Biological activity of the thyroid TRK-T3 oncogene requires signalling through Shc

et al. 2002

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The thyroid TRK-T3 oncogene, produced by a chromosomal translocation, is a chimeric, constitutively activated version of the NTRK1/NGF receptor and it is able to transform NIH3T3 cells and differentiate PC12 cells. TRK-T3 oncoprotein triggers multiple signal transduction pathways. Among others, TRK-T3 binds and phosphorylates the Shc and SNT1/FRS2 adaptor proteins both involved in coupling the receptor tyrosine kinase to the mitogen-activated protein kinase pathway by recruiting Grb2/SOS. We were interested in defining the role of Shc in the oncogenesis by TRK-T3. The mutation of TRK-T3 tyrosine 291, docking site for both Shc and FRS2, abrogates the oncogene biological activity. To directly explore the role of Shc we used the ShcY317F mutant, which carries the mutation of a tyrosine residue involved in Grb2 recruitment. We demonstrated that the ShcY317F mutant exerts an inhibitory effect on TRK-T3 transforming activity. Such effect can be modulated by the amount of ShcY317F protein and affects the viability of cells expressing TRK-T3 by means of a mechanism involving apoptosis. Our results indicate a definitive role of the adaptor protein Shc in TRK-T3 transforming activity.

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Section: Discussionsupporting

confidence: 92%

Biological activity of the thyroid TRK-T3 oncogene requires signalling through Shc

et al. 2002

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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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“…Phosphorylation of only the second tyrosine would be predicted to create a high-affinity docking site for the Src homology 2-containing adapter protein Shc [20]. Recruitment of Shc may tie WC1 activation into the Ras-MAPK or the phosphatidylinositol 3-kinase/Akt pathways [32]. The YEEL motif in WC1 may also mediate WC1 endocytosis if the tyrosine is unphosphorylated [33]; although, we did not observe a change in the surface expression of WC1 when the tyrosine in the YEEL motif was mutated to phenylalanine.…”

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confidence: 99%

Tyrosine phosphorylation of scavenger receptor cysteine‐rich WC1 is required for the WC1‐mediated potentiation of TCR‐induced T‐cell proliferation

et al. 2009

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Workshop cluster 1 (WC1) molecules are transmembrane glycoproteins uniquely expressed by cd T cells. They belong to the scavenger receptor cysteine-rich superfamily and are encoded by a multi-gene family, which is divided on the basis of antibody reactivity, into three groups, WC1.1, WC1.2, and WC1.3. The potential role of WC1 as a co-stimulatory molecule for the cd TCR is suggested by the presence of several tyrosinebased motifs in their intracellular domains. In this study, we found that WC1 was constitutively phosphorylated in ex vivo bovine cd T cells and associated with src family tyrosine kinases. Crosslinking of WC1 molecules resulted in an increase in WC1 phosphorylation and co-crosslinking of WC1 and cd TCR together prolonged WC1 phosphorylation. We identified the second tyrosine residue as the primary phosphorylation target in WC1.1 and WC1.2 intracellular sequences in both in vitro and in vivo assays. The cytoplasmic tails of WC1.1 and WC1.2 were phosphorylated on serine and PKC activity was required for PMA-induced endocytosis of WC1.1 or WC1.2. We found that phosphorylation of the second tyrosine in the WC1 cytoplasmic domain was required for the WC1-mediated potentiation of TCR-induced T-cell proliferation, suggesting that WC1 acts as a co-stimulatory molecule for cd TCR.Key words: Bovine . Cell surface molecules . gd T cells . Signal transduction IntroductionIn adult chickens, ruminants and pigs, unlike in mice and humans, gd T cells can constitute 30% of total PBMC [1]. A majority of these gd T cells in ruminants bear the glycoprotein lineage marker Workshop cluster 1 (WC1) on their surface. Based on the profiles of their gene expression, WC1 1 gd T cells of cattle represent the inflammatory population, whereas WC1 À gd T cells are regulatory cells [2,3]. WC1, a member of the scavenger receptor cysteine-rich (SRCR) superfamily, is categorized into group B along with CD5, CD6, and CD163, based on the organization of cysteine residues in its extracellular SRCR domains [4]. Like the SRCR family member SpSRCR, which is expressed in the immune cells of the purple sea urchin [5], WC1 molecules are products of a large gene family, and thus have the potential to increase the diversity of immune responses independently of the adaptive immune response receptor, i.e. the TCR.Bovine gd T cells express at least three known variants, WC1.1, WC1.2, and WC1.3, which are defined by antibodies recognizing unknown epitopes on their SRCR domains [6]. WC1.1 and WC1.2 are expressed on two mostly non-overlapping subsets of bovine gd T cells, and WC1.3 is expressed on a small 254subpopulation of WC1.1 1 cells. Cytokine production and cellular proliferation in response to stimulation vary according to the forms of WC1 expressed by gd T cells [7]. Ex vivo WC1.1 1 gd T cells, but not WC1.2 1 gd T cells, proliferate well to the gd T-cell antigens of Leptospira, and produce IFN-g in response to either antigen or 8].The correlation of the expression of a variable WC1 gene product with a cellular immune response to antigen su...

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New Role for Shc in Activation of the Phosphatidylinositol 3-Kinase/Akt Pathway

Cited by 273 publications

References 64 publications

Biological activity of the thyroid TRK-T3 oncogene requires signalling through Shc

Biological activity of the thyroid TRK-T3 oncogene requires signalling through Shc

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

Tyrosine phosphorylation of scavenger receptor cysteine‐rich WC1 is required for the WC1‐mediated potentiation of TCR‐induced T‐cell proliferation

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