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Prepublished online as a Blood First Edition Paper on August 14, 2003; DOI 10.1182/blood-2003-06-1999.
Submitted June 19, 2003
Accepted July 28, 2003
The phosphoserine-585-dependent pathway of the GM-CSF/IL-3/IL-5 receptors mediates hemopoietic cell survival through activation of NF- B and induction of bcl-2
Mark A Guthridge, Emma F Barry, Fernando A Felquer, Barbara J McClure, Frank C Stomski, Hayley S Ramshaw, and Angel F Lopez*
Division of Human Immunology, Institute of Medical and Veterinary Science (IMVS), Adelaide, SA, Australia
* Corresponding author; email: angel.lopez{at}imvs.sa.gov.au.
We have recently identified a novel mechanism of hemopoietic cell survival that involves site-specific serine phosphorylation of the common beta subunit ( c) of the GM-CSF, IL-3 and IL-5 receptors. However, the downstream components of this pathway are not known, nor is it clear its relationship to survival signals triggered by tyrosine phosphorylation of the receptor. We have now found that phosphorylation of Ser585 of c in response to GM-CSF recruited 14-3-3 and PI 3-kinase to the receptor whilst phosphorylation of the neighbouring Tyr577 within this "viability domain" promoted the activation of both Shc and Ras. These are independent processes as demonstrated by the intact reactivity of phosphospecific anti-Ser585 and anti-Tyr577 antibodies on the CTL EN mutants cTyr577Phe and cSer585Gly respectively. Importantly, whilst mutants in which either Ser585 (cSer585Gly) or all tyrosines (cF8) were substituted showed a defect in Akt phosphorylation, NF- B activation, bcl-2 induction and cell survival, the mutant cTyr577Phe was defective in Shc, Ras and 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 hemopoietic cell survival, are initially independent of each other, and converge on NF-B to promote bcl-2 expression.
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