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

Guthridge, Mark A, Barry, Emma F, Felquer, Fernando A, McClure, Barbara J, Stomski, Frank C, Ramshaw, Hayley and Lopez, Angel F 2004, The phosphoserine-585-dependent pathway of the GM-CSF/IL-3/IL-5 receptors mediates hematopoietic cell survival through activation of NF-kappa B and induction of bcl-2, BLOOD, vol. 103, no. 3, pp. 820-827, doi: 10.1182/blood-2003-06-1999.

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Title The phosphoserine-585-dependent pathway of the GM-CSF/IL-3/IL-5 receptors mediates hematopoietic cell survival through activation of NF-kappa B and induction of bcl-2
Author(s) Guthridge, Mark AORCID iD for Guthridge, Mark A orcid.org/0000-0002-0536-3471
Barry, Emma F
Felquer, Fernando A
McClure, Barbara J
Stomski, Frank C
Ramshaw, Hayley
Lopez, Angel F
Journal name BLOOD
Volume number 103
Issue number 3
Start page 820
End page 827
Total pages 8
Publisher AMER SOC HEMATOLOGY
Place of publication United States
Publication date 2004-02-01
ISSN 0006-4971
1528-0020
Keyword(s) Science & Technology
Life Sciences & Biomedicine
Hematology
MULTIPLE SIGNALING PATHWAYS
COMMON BETA-CHAIN
FACTOR GM-CSF
TYROSINE RESIDUES
THROMBOPOIETIN RECEPTOR
SERINE PHOSPHORYLATION
DIFFERENTIATION
PROLIFERATION
EXPRESSION
INTERACTS
Summary AbstractWe 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 βcSer585Gly, 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.
Language eng
DOI 10.1182/blood-2003-06-1999
Indigenous content off
Field of Research 1102 Cardiorespiratory Medicine and Haematology
1103 Clinical Sciences
1114 Paediatrics and Reproductive Medicine
HERDC Research category C1 Refereed article in a scholarly journal
Persistent URL http://hdl.handle.net/10536/DRO/DU:30134403

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