Tyrosine phosphorylation of Shc is not required for proliferation or viability signaling by granulocyte-macrophage colony-stimulating factor in hematopoietic cell lines
Durstin, M.; Inhorn, R.C.; Griffin, J.D.
Journal of Immunology 157(2): 534-540
1996
ISSN/ISBN: 0022-1767 PMID: 8752899 Document Number: 457333
The receptor for human granulocyte-macrophage (GM)-CSF (GMR) is a heterodimer, consisting of an alpha-chain (GMR-alpha) and a beta-chain (GMR-beta). While GMR-alpha is capable of binding GM-CSF, GMR-beta is necessary for signal transduction. Phosphorylation of one or more tyrosine residues in GMR-beta is an early event in signaling. We have recently demonstrated that tyrosine 750 (Y750) in GMR-beta is a site of GM-CSF-induced phosphorylation and this site may contribute to the maintenance of cellular viability in response to GM-CSF. To investigate possible contributions made by additional GMR-beta cytoplasmic tyrosine residues to receptor function, we mutated other selected tyrosine residues to phenylalanine and tested for any defects in signaling. in the present study, we show that Y577 is required for phosphorylation of Shc and an Shc-associated p140 in response to GM-CSF. Y577 is also required for association of Shc with GRB2. Y577 does not appear to be necessary for GM-CSF-induced proliferation and survival. GMR-beta with a mutated Y577 is able to transduce signals leading to the activation of the Raf-1 pathway and the Jak-Stat pathway. Interestingly, mutation of Y750 reduced detectable GM-CSF-induced tyrosine phosphorylation of GMR-beta, suggesting that the reduction of Shc phosphorylation associated with that mutant might be actually due to a failure to phosphorylate Y577. These data indicate that the phosphorylation of Shc in response to GM-CSF is not required for proliferation or viability signaling in these cells.