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Molecular and Cellular Biology, June 2003, p. 3884-3896, Vol. 23, No. 11
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.11.3884-3896.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Two Distinct Phosphorylation Pathways Have Additive Effects on Abl Family Kinase Activation

Keith Q. Tanis,1 Darren Veach,2 Henry S. Duewel,3 William G. Bornmann,2 and Anthony J. Koleske1*

Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520,1 Organic Synthesis Core Facility, Sloan-Kettering Institute for Cancer Research, New York, New York 10021,2 MDS Proteomics, Toronto, Ontario M9W 7H4, Canada3

Received 7 November 2002/ Returned for modification 17 December 2002/ Accepted 4 March 2003

The activities of the related Abl and Arg nonreceptor tyrosine kinases are kept under tight control in cells, but exposure to several different stimuli results in a two- to fivefold stimulation of kinase activity. Following the breakdown of inhibitory intramolecular interactions, Abl activation requires phosphorylation on several tyrosine residues, including a tyrosine in its activation loop. These activating phosphorylations have been proposed to occur either through autophosphorylation by Abl in trans or through phosphorylation of Abl by the Src nonreceptor tyrosine kinase. We show here that these two pathways mediate phosphorylation at distinct sites in Abl and Arg and have additive effects on Abl and Arg kinase activation. Abl and Arg autophosphorylate at several sites outside the activation loop, leading to 5.2- and 6.2-fold increases in kinase activity, respectively. We also find that the Src family kinase Hck phosphorylates the Abl and Arg activation loops, leading to an additional twofold stimulation of kinase activity. The autoactivation pathway may allow Abl family kinases to integrate or amplify cues relayed by Src family kinases from cell surface receptors.

* Corresponding author. Mailing address: Yale School of Medicine, SHMC-E31, 333 Cedar St., New Haven, CT 06520. Phone: (203) 785-5624. Fax: (203) 785-7979. E-mail: anthony.koleske{at}yale.edu.

Molecular and Cellular Biology, June 2003, p. 3884-3896, Vol. 23, No. 11
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.11.3884-3896.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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