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Originally published In Press as doi:10.1074/jbc.M410658200 on January 4, 2005

J. Biol. Chem., Vol. 280, Issue 11, 10318-10325, March 18, 2005
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Mitotic Phosphorylation Rescues Abl from F-actin-mediated Inhibition*

Pamela J. Woodring{ddagger}§, Tony Hunter{ddagger}, and Jean Y. J. Wang§||

From the {ddagger}Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037-1099 and §Division of Biological Sciences and the Moores Cancer Center, University of California, San Diego, La Jolla, California 92093-0322

We have previously shown that F-actin exerts a negative effect on Abl tyrosine kinase activity. This inhibition results from a direct association of F-actin with the C terminus of Abl and accounts, in part, for the loss of Abl activity in detached fibroblasts. We report here that Abl from mitotic cells or cells treated with the protein phosphatase inhibitor okadaic acid remains active when detached from the extracellular matrix. Aspartic acid substitution of Thr566, which is phosphorylated in mitotic or okadaic acid-treated cells, is sufficient to abolish F-actin-mediated inhibition and to maintain Abl activity despite cell detachment. A recent crystal structure of the Abl N-terminal region has revealed autoinhibitory interactions among the Src homology 3 (SH3), SH2, and kinase domains. We found that deletion of the SH2 domain also abolished the negative effect of F-actin on kinase activity. Immediately following the kinase domain in Abl is a proline-rich linker (PRL) that binds to several SH3 adaptor proteins. Interestingly, binding of the Crk N-terminal SH3 domain to the PRL also disrupted F-actin-mediated inhibition of Abl kinase. These results suggest that F-actin may reinforce the autoinhibitory interactions to regulate Abl kinase and that inhibition can be relieved through phosphorylation and/or protein interactions with the Abl PRL region.


Received for publication, September 16, 2004 , and in revised form, December 17, 2004.

* This work was supported by a postdoctoral fellowship from the NCI, National Institutes of Health CA76710 (to P. J. W.) and National Institutes of Health Grants HL57900 (to J. Y. J. W.) and CA82863 (to T. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

A Frank and Else Schilling American Cancer Society Research Professor.

|| Herbert Stern Endowed Chair of Biology, University of California, San Diego. To whom correspondence should be addressed: Division of Biological Sciences and the Moores Cancer Center, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0322. Tel.: 858-534-6253; Fax: 858-822-2002; E-mail: jywang{at}ucsd.edu.


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