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

Ramshaw, Hayley S, Guthridge, Mark A, Stomski, Frank C, Barry, Emma F, Ooms, Lisa, Mitchell, Christina A, Begley, C Glenn and Lopez, Angel F 2007, The Shc-binding site of the beta(c) subunit of the GM-CSF/IL-3/IL-5 receptors is a negative regulator of hematopoiesis, BLOOD, vol. 110, no. 10, pp. 3582-3590, doi: 10.1182/blood-2007-01-070391.

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Title The Shc-binding site of the beta(c) subunit of the GM-CSF/IL-3/IL-5 receptors is a negative regulator of hematopoiesis
Author(s) Ramshaw, Hayley S
Guthridge, Mark AORCID iD for Guthridge, Mark A orcid.org/0000-0002-0536-3471
Stomski, Frank C
Barry, Emma F
Ooms, Lisa
Mitchell, Christina A
Begley, C Glenn
Lopez, Angel F
Journal name BLOOD
Volume number 110
Issue number 10
Start page 3582
End page 3590
Total pages 9
Publisher AMER SOC HEMATOLOGY
Place of publication United States
Publication date 2007-11-15
ISSN 0006-4971
1528-0020
Keyword(s) Science & Technology
Life Sciences & Biomedicine
Hematology
COLONY-STIMULATING FACTOR
SIGNALING SOCS PROTEINS
TYROSINE PHOSPHORYLATION
IL-3 RECEPTOR
C CHAIN
G-CSF
SERINE PHOSPHORYLATION
MULTIPLE CYTOKINES
MICE LACKING
ACTIVATION
Summary Abstract Tyrosine and serine phosphorylation of the common β chain (βc) of the granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (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 βc to recruit Shc–PI-3 kinase (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 SH2-containing inositol 5′-phosphatase (SHIP) from βc. Fetal liver cells from βc/βIL-3−/− mice expressing human GM-CSF receptor α chain and βc 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 unrecognized negative signaling role for Tyr577 in βc and demonstrate that uncoupling Shc from cytokine receptors enhances PI3K signaling as well as survival and proliferation.
Language eng
DOI 10.1182/blood-2007-01-070391
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:30134409

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