A novel pathway from phosphorylation of tyrosine residues 239/240 of Shc, contributing to suppress apoptosis by IL‐3.

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.

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