The phosphoserine-585-dependent pathway of the GM-CSF/IL-3/IL-5 receptors mediates hematopoietic cell survival through activation of NF-κB and induction of bcl-2

Mark A. Guthridge, Emma F. Barry, Fernando A. Felquer, Barbara J. McClure, Frank C. Stomski, Hayley Ramshaw, Angel F. Lopez

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Abstract

We have recently identified a novel mechanism of hematopoietic cell survival that involves site-specific serine phosphorylation of the common beta subunit (βc) of the granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5 receptors. However, the downstream components of this pathway are not known, nor is its relationship to survival signals triggered by tyrosine phosphorylation of the receptor clear. We have now found that phosphorylation of Ser585 of βc in response to GM-CSF recruited 14-3-3 and phosphatidyl inositol 3-OH kinase (PI 3-kinase) to the receptor, while phosphorylation of the neighboring Tyr577 within this "viability domain" promoted the activation of both Src homology and collagen (Shc) and Ras. These are independent processes as demonstrated by the intact reactivity of phosphospecific anti-Ser585 and anti-Tyr577 antibodies on the cytotoxic T-lymphocyte-ecotrophic retroviral receptor neomycin (CTL-EN) mutants βcTyr577Phe and β cSer585Gly, respectively. Importantly, while mutants in which either Ser585 (βcSer585Gly) or all tyrosines (βcF8) were substituted showed a defect in Akt phosphorylation, nuclear factor κB (NF-κB) activation, bcl-2 induction, and cell survival, the mutant βcTyr577Phe was defective in Shc, Ras, and extracellular signal-related kinase (ERK) activation, but supported CTL-EN cell survival in response to GM-CSF. These results demonstrate that both serine and tyrosine phosphorylation pathways play a role in hematopoietic cell survival, are initially independent of each other, and converge on NF-κB to promote bcl-2 expression.

Original languageEnglish
Pages (from-to)820-827
Number of pages8
JournalBlood
Volume103
Issue number3
DOIs
Publication statusPublished - 1 Feb 2004

ASJC Scopus subject areas

  • Hematology

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