Premium
A novel pathway from phosphorylation of tyrosine residues 239/240 of Shc, contributing to suppress apoptosis by IL‐3.
Author(s) -
Gotoh N.,
Tojo A.,
Shibuya M.
Publication year - 1996
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1002/j.1460-2075.1996.tb01008.x
Subject(s) - biology , phosphorylation , tyrosine , protein tyrosine kinases , apoptosis , microbiology and biotechnology , tyrosine phosphorylation , signal transduction , cancer research , tyrosine kinase , genetics , biochemistry
Interleukin 3 (IL‐3) not only induces DNA synthesis of haematopoietic cells but also maintains their viability by suppressing apoptosis. IL‐3 stimulates tyrosine phosphorylation of the Shc adaptor protein and thereby formation of a complex of Shc with Grb2 at phosphorylated tyrosine (Y) residue 317‐Shc. This pathway is implicated in Ras/mitogen‐activated protein kinase (MAPK) activation towards c‐fos gene expression. We examined the possible involvement of Shc in the antiapoptotic activity of IL‐3. Conditional overexpression of the Shc SH2 domain, a dominant‐negative mutant of Shc, was found to induce apoptosis of IL‐3‐dependent Ba/F3 cells along with a reduction of c‐myc gene expression. Apoptosis was rescued by the exogenously introduced c‐myc gene. Since we identify novel tyrosine phosphorylation sites of Shc: Y239 and Y240, their role on cell survival was tested by mutational analysis. Ba/F3 cells expressing mutant Shc Y317F, which is unable to stimulate efficiently the Ras pathway, still showed resistance to apoptosis. However, cells expressing Shc Y239/240F, which is able to stimulate the Ras pathway, were sensitive to apoptosis. In these cells, induction of the c‐myc gene was reduced. These findings suggest that a new signalling pathway for cell survival is generated from Y239/240 of Shc to the nuclei involving c‐myc gene expression.