The Shc-binding site of the ?c subunit of the GM-CSF/IL-3/IL-5 receptors is a negative regulator of hematopoiesis

Hayley S Ramshaw, Mark A Guthridge, Frank C Stomski, Emma F Barry, Lisa Michelle Ooms, Christina Anne Mitchell, C Glenn Begley, Angel F Lopez

Research output: Contribution to journalArticleResearchpeer-review

16 Citations (Scopus)

Abstract

Tyrosine and Serine phosphorylation of the common beta chain (betac) of the granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin (IL)-3 and IL-5 receptors is widely viewed as a general mechanism that provides positive inputs by coupling the receptor to signaling pathways that stimulate several cellular functions. We show here that despite the known action of Tyr577 in betac to recruit Shc-PI3K pathway members, Tyr577 plays, surprisingly, a negative regulatory role in cell function and, that this is mediated, at least in part, through the uncoupling of SHIP from betac. Fetal liver cells from betac/betaIL-3(-/-) mice expressing human GM-CSF receptor alpha chain and betac Tyr577Phe mutant showed enhanced colony formation and expansion of progenitor cells in response to GM-CSF. Dissection of these activities revealed that basal survival was increased, as well as cytokine-stimulated proliferation. As expected the recruitment and activation of Shc was abolished, but interestingly, Gab-2 and Akt phosphorylation increased. Significantly, the activation of PI3K was enhanced and prolonged, accompanied by loss of SHIP activity. These results reveal a previously unrecognised negative signalling role for Tyr577 in betac and demonstrate that uncoupling Shc from cytokine receptors enhances PI3K signalling as well as survival and proliferation.
Original languageEnglish
Pages (from-to)3582 - 3590
Number of pages9
JournalBlood
Volume110
Issue number10
Publication statusPublished - 2007

Cite this