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J Biol Chem, Vol. 274, Issue 13, 8917-8924, March 26, 1999

Interactions between Two Cytoskeleton-associated Tyrosine Kinases: Calcium-dependent Tyrosine Kinase and Focal Adhesion Tyrosine Kinase

Xiong Li, Ruth C. Dy, William G. Cance^§, Lee M. Graves^¶, and H. Shelton Earp^¶

From the  Lineberger Comprehensive Cancer Center, the Departments of ^¶ Pharmacology,  Medicine, and ^§ Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295

The calcium-dependent tyrosine kinase (CADTK), also known as Pyk2/RAFTK/CAK/FAK2, is a cytoskeleton-associated tyrosine kinase. We compared CADTK regulation with that of the highly homologous focal adhesion tyrosine kinase (FAK). First, we generated site-specific CADTK mutants. Mutation of Tyr⁴⁰² eliminated autophosphorylation and significantly decreased kinase activity. Mutation of Tyr⁸⁸¹, a putative Src kinase phosphorylation site predicted to bind Grb2, had little effect on CADTK regulation. Src family tyrosine kinases resulted in CADTK tyrosine phosphorylation even when co-expressed with the Tyr⁴⁰²/Tyr⁸⁸¹ double mutant, suggesting that Src/Fyn etc. phosphorylate additional tyrosine residues. Interestingly, CADTK tyrosine-phosphorylated FAK when both were transiently expressed, but FAK did not phosphorylate CADTK. Biochemical experiments confirmed direct CADTK phosphorylation of FAK. This phosphorylation utilized tyrosine residues other than Tyr³⁹⁷, Tyr⁹²⁵, or Tyr⁵⁷⁶/Tyr⁵⁷⁷, suggesting that new SH2-binding sites might be created by CADTK-dependent FAK phosphorylation. Last, expression of the CADTK carboxyl terminus (CRNK) abolished CADTK but not FAK autophosphorylation. In contrast, FAK carboxyl terminus overexpression inhibited both FAK and CADTK autophosphorylation, suggesting that a FAK-dependent cytoskeletal function may be necessary for CADTK activation. Thus, CADTK and FAK, which both bind to some, but not necessarily the same, cytoskeletal elements, may be involved in coordinate regulation of cytoskeletal structure and signaling.

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