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Molecular and Cellular Biology, December 1999, p. 8314-8325, Vol. 19, No. 12
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Characterization of a Novel Member of the DOK Family That Binds and Modulates Abl Signaling

Feng Cong,1 Bing Yuan,2 and Stephen P. Goff3,4,*

Department of Biological Sciences,1 Integrated Program in Cellular, Molecular and Biophysical Studies,2 Howard Hughes Medical Institute,3 and Department of Biochemistry and Molecular Biophysics,4 Columbia University College of Physicians and Surgeons, New York, New York 10032

Received 25 May 1999/Returned for modification 30 June 1999/Accepted 7 September 1999

A novel member of the p62dok family of proteins, termed DOKL, is described. DOKL contains features of intracellular signaling molecules, including an N-terminal PH (pleckstrin homology) domain, a central PTB (phosphotyrosine binding) domain, and a C-terminal domain with multiple potential tyrosine phosphorylation sites and proline-rich regions, which might serve as docking sites for SH2- and SH3-containing proteins. The DOKL gene is predominantly expressed in bone marrow, spleen, and lung, although low-level expression of the RNA can also be detected in other tissues. DOKL and p62dok bind through their PTB domains to the Abelson tyrosine kinase in a kinase-dependent manner in both yeast and mammalian cells. DOKL is phosphorylated by the Abl tyrosine kinase in vivo. In contrast to p62dok, DOKL lacks YxxP motifs in the C terminus and does not bind to Ras GTPase-activating protein (RasGAP) upon phosphorylation. Overexpression of DOKL, but not p62dok, suppresses v-Abl-induced mitogen-activated protein (MAP) kinase activation but has no effect on constitutively activated Ras- and epidermal growth factor-induced MAP kinase activation. The inhibitory effect requires the PTB domain of DOKL. Finally, overexpression of DOKL in NIH 3T3 cells inhibits the transforming activity of v-Abl. These results suggest that DOKL may modulate Abl function.

* Corresponding author. Mailing address: Room 1127 HHSC, Columbia University College of Physicians and Surgeons, 701 West 168 St., New York, NY 10032. Phone: (212) 305-3794. Fax: (212) 305-8692. E-mail: goff{at}cuccfa.columbia.edu.

Molecular and Cellular Biology, December 1999, p. 8314-8325, Vol. 19, No. 12
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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