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J. Biol. Chem., Vol. 279, Issue 18, 19335-19349, April 30, 2004

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Pleckstrin Homology and Phosphotyrosine-binding Domain-dependent Membrane Association and Tyrosine Phosphorylation of Dok-4, an Inhibitory Adapter Molecule Expressed in Epithelial Cells^*

Arda Bedirian, Cindy Baldwin, Jun-ichi Abe, Tomoko Takano¶, and Serge Lemay¶||

From the Department of Medicine, Division of Nephrology, McGill University Health Centre, Montreal, Quebec H3A 2B4, Canada and the Center for Cardiovascular Research, University of Rochester Medical Center, Rochester, New York 14642

Dok-like adapter molecules represent an expanding family of pleckstrin homology (PH) and phosphotyrosine-binding (PTB) domain-containing tyrosine kinase substrates with negative regulatory functions in hematopoietic cell signaling. In a search for nonhematopoietic counterparts to Dok molecules, we identified and characterized Dok-4, a recently cloned member of the family. dok-4 mRNA was strongly expressed in nonhematopoietic organs, particularly the intestine, kidney, and lung, whereas both mRNA and protein were expressed at high levels in cells of epithelial origin. In Caco-2 human colon cancer cells, endogenous Dok-4 underwent tyrosine phosphorylation in response to pervanadate stimulation. In transfected COS cells, Dok-4 was a substrate for the cytosolic tyrosine kinases Src and Fyn as well as for Jak2. Dok-4 could also be phosphorylated by the receptor tyrosine kinase Ret but not by platelet-derived growth factor receptor- or IGF-IR. In both mammalian cells and yeast, Dok-4 was constitutively localized at the membrane in a manner that required both its PH and PTB domains. The PH and PTB domains of Dok-4 were also required for tyrosine phosphorylation of Dok-4 by Fyn and Ret. Finally, wild type Dok-4 strongly inhibited activation of Elk-1 induced by either Ret or Fyn. The attenuation of this inhibitory effect by deletion of the PH domain and its restoration by the addition of a myristoylation signal suggested an important role for constitutive membrane localization of Dok-4. In summary, Dok-4 is a constitutively membrane-localized adapter molecule that may function as an inhibitor of tyrosine kinase signaling in epithelial cells.

Received for publication, September 26, 2003 , and in revised form, January 15, 2004.

^* This work was supported by grants from the Kidney Foundation of Canada and the Canadian Institutes of Health Research (CIHR) (to S. L. and T. T.) and by National Institutes of Health RO1 Grant HL66919 (to J. A.). 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.

^¶ Recipients of a CIHR New Investigator Award.

^|| To whom correspondence should be addressed: McGill University, Lyman-Duff Bldg., Rm. 228, 3775 University St., Montreal, Quebec H3A 2B4, Canada. Tel.: 514-398-2762; Fax: 514-843-2815; E-mail: serge.lemay{at}mcgill.ca.

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