Shc proteins participate in a variety of processes regulating cell proliferation, survival and apoptosis. The two ubiquitously expressed isoforms, p52Shc/p46Shc, couple tyrosine kinase receptors to Ras by recruiting Grb2/Sos complexes to a membrane-proximal localization. Tyrosine residues 239/240 and 317 become phosphorylated following receptor engagement and, as such, form two Grb2 binding sites, which have been proposed to be differentially coupled to Myc-dependent survival and to fos-dependent proliferation, respectively. Here, we have addressed the individual function of YY239/240 and Y317 in T-cell antigen receptor (TCR) signaling. We show that p52Shc is phosphorylated on both YY239/240 and Y317 following TCR engagement. Mutation of either YY239/240 or Y317 results in impaired interaction with Grb2 and inhibition of Ras/MAP kinase activation and CD69 induction, supporting a role for both Grb2 binding sites in this function. Substitution of either YY239/240 or Y317 also results in a defective activation of Rac and the coupled stress kinases JNK and p38. Furthermore, mutation of Y317 or, to a larger extent, of YY239/240, results in increased activation-induced cell death, which in cells expressing the FF239/240 mutant is accompanied by impaired TCR-dependent c-myc transcription. The data underline a pleiotropic and nonredundant role of Shc, mediated by both YY239/240 and Y317, in T-cell activation and survival.

Patrussi, L., Savino, M.T., Pellegrini, M., ROSSI PACCANI, S., Migliaccio, E., Plyte, S., et al. (2005). Cooperation and selectivity of the two Grb2 binding sites of p52Shc in T cell antigen receptor signaling to Ras family GTPases and Myc dependent survival. ONCOGENE, 24, 2218-2228.

Cooperation and selectivity of the two Grb2 binding sites of p52Shc in T cell antigen receptor signaling to Ras family GTPases and Myc dependent survival

PATRUSSI, LAURA;SAVINO, MARIA TERESA;PELLEGRINI, MICHELA;ROSSI PACCANI, SILVIA;BALDARI, COSIMA
2005-01-01

Abstract

Shc proteins participate in a variety of processes regulating cell proliferation, survival and apoptosis. The two ubiquitously expressed isoforms, p52Shc/p46Shc, couple tyrosine kinase receptors to Ras by recruiting Grb2/Sos complexes to a membrane-proximal localization. Tyrosine residues 239/240 and 317 become phosphorylated following receptor engagement and, as such, form two Grb2 binding sites, which have been proposed to be differentially coupled to Myc-dependent survival and to fos-dependent proliferation, respectively. Here, we have addressed the individual function of YY239/240 and Y317 in T-cell antigen receptor (TCR) signaling. We show that p52Shc is phosphorylated on both YY239/240 and Y317 following TCR engagement. Mutation of either YY239/240 or Y317 results in impaired interaction with Grb2 and inhibition of Ras/MAP kinase activation and CD69 induction, supporting a role for both Grb2 binding sites in this function. Substitution of either YY239/240 or Y317 also results in a defective activation of Rac and the coupled stress kinases JNK and p38. Furthermore, mutation of Y317 or, to a larger extent, of YY239/240, results in increased activation-induced cell death, which in cells expressing the FF239/240 mutant is accompanied by impaired TCR-dependent c-myc transcription. The data underline a pleiotropic and nonredundant role of Shc, mediated by both YY239/240 and Y317, in T-cell activation and survival.
Patrussi, L., Savino, M.T., Pellegrini, M., ROSSI PACCANI, S., Migliaccio, E., Plyte, S., et al. (2005). Cooperation and selectivity of the two Grb2 binding sites of p52Shc in T cell antigen receptor signaling to Ras family GTPases and Myc dependent survival. ONCOGENE, 24, 2218-2228.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/24241
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