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First published online 30 September 2008
doi: 10.1242/jcs.035691

Journal of Cell Science 121, 3335-3346 (2008)
Published by The Company of Biologists 2008
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Research Article

SHP-2 is a novel target of Abl kinases during cell proliferation

Sayan Mitra1, Carol Beach2, Gen-Sheng Feng3 and Rina Plattner1,*

1 Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington, KY 40536, USA
2 Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA
3 Burnham Institute for Medical Research, La Jolla, CA 92037, USA

* Author for correspondence (e-mail: rplat2{at}uky.edu)

Accepted 14 July 2008

Previously, we showed that Abl family tyrosine kinases are activated by growth factors, and Abl is required for transition from G1 to S phase during PDGF-mediated proliferation. Here, we show that the SHP-2 tyrosine phosphatase, which acts to promote proliferation in response to cytokines and growth factors, is a novel substrate of endogenous Abl kinases during growth factor-mediated cellular proliferation. Using a pharmacological inhibitor and RNAi, we show that endogenous Abl kinases phosphorylate SHP-2 on Y580, and induce sustained activation of ERK kinases in response to growth factor stimulation in fibroblasts. Consistent with these data, SHP-2 is required for Abl-dependent PDGF-mediated proliferation since expression of an activated form of SHP-2 rescues the ability of Abl-Arg null fibroblasts to transit from G1 to S phase, whereas inhibition of SHP-2 signaling reduces the ability of Abl kinases to rescue the proliferation defect. Abl kinases also indirectly mediate phosphorylation of SHP-2 on Y63 and Y279, which are frequent sites of germline mutation in two cancer susceptibility syndromes. Significantly, we demonstrate that phosphorylation of SHP-2 on Y279 downregulates growth factor-induced sustained ERK activation and proliferation, supporting a role for Abl kinases not only in potentiating growth factor-mediated SHP-2 signaling, but also in negative-feedback regulation.

Key words: Abl, Arg, SHP-2, Proliferation, ERK


Related articles in JCS:

Abl and SHP-2: proliferative partners

JCS 2008 121: 2002. [Full Text]  





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