p66SHC promotes apoptosis and antagonizes mitogenic signaling in T cells.
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.
Pacini
Sonia
S
Department of Evolutionary Biology, University of Siena, 53100 Siena, Italy.
Pellegrini
Michela
M
Migliaccio
Enrica
E
Patrussi
Laura
L
Ulivieri
Cristina
C
Ventura
Andrea
A
Carraro
Fabio
F
Naldini
Antonella
A
Lanfrancone
Luisa
L
Pelicci
Piergiuseppe
P
Baldari
Cosima T
CT
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division; D053222:Fas Ligand Protein; D051380:GRB2 Adaptor Protein; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006801:Humans; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008934:Mitogens / Q000494:pharmacology*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction / Q000187:drug effects*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; D008562:Membrane Glycoproteins; D008934:Mitogens; D011506:Proteins; D012333:RNA, Messenger; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; C497262:Zap70 protein, mouse; D020928:Mitogen-Activated Protein Kinases