p66SHC promotes apoptosis and antagonizes mitogenic signaling in T cells

Mol Cell Biol. 2004 Feb;24(4):1747-57. doi: 10.1128/MCB.24.4.1747-1757.2004.

Abstract

Of the three Shc isoforms, p66Shc is responsible for fine-tuning p52/p46Shc signaling to Ras and has been implicated in apoptotic responses to oxidative stress. Here we show that human peripheral blood lymphocytes and mouse thymocytes and splenic T cells acquire the capacity to express p66Shc in response to apoptogenic stimulation. Using a panel of T-cell transfectants and p66Shc(-/-) T cells, we show that p66Shc expression results in increased susceptibility to apoptogenic stimuli, which depends on Ser36 phosphorylation and correlates with an altered balance in apoptosis-regulating gene expression. Furthermore, p66Shc blunts mitogenic responses to T-cell receptor engagement, at least in part by transdominant inhibition of p52Shc signaling to Ras/mitogen-activated protein kinases, in an S36-dependent manner. The data highlight a novel interplay between p66Shc and p52Shc in the control of T-cell fate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Adaptor Proteins, Vesicular Transport / genetics
  • Adaptor Proteins, Vesicular Transport / metabolism*
  • Animals
  • Apoptosis* / drug effects
  • Cell Division
  • Fas Ligand Protein
  • GRB2 Adaptor Protein
  • Gene Deletion
  • Gene Expression Regulation
  • Humans
  • Jurkat Cells
  • Membrane Glycoproteins / genetics
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism
  • Mitogens / pharmacology*
  • Phosphorylation
  • Phosphotyrosine / metabolism
  • Protein Binding
  • Protein-Tyrosine Kinases / metabolism
  • Proteins / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Shc Signaling Adaptor Proteins
  • Signal Transduction / drug effects*
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • T-Lymphocytes / cytology
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / metabolism
  • ZAP-70 Protein-Tyrosine Kinase

Substances

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • FASLG protein, human
  • Fas Ligand Protein
  • Fasl protein, mouse
  • GRB2 Adaptor Protein
  • GRB2 protein, human
  • Grb2 protein, mouse
  • Membrane Glycoproteins
  • Mitogens
  • Proteins
  • RNA, Messenger
  • SHC1 protein, human
  • Shc Signaling Adaptor Proteins
  • Shc1 protein, mouse
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Phosphotyrosine
  • Protein-Tyrosine Kinases
  • ZAP-70 Protein-Tyrosine Kinase
  • ZAP70 protein, human
  • Zap70 protein, mouse
  • Mitogen-Activated Protein Kinases