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Published online 17 May 2004. doi:10.1083/jcb.200312171
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 165, Number 4, 493-503
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Article

 c-Abl phosphorylates Dok1 to promote filopodia during cell spreading

Pamela J. Woodring1, Jill Meisenhelder1, Sam A. Johnson1, Guo-Lei Zhou2, Jeffrey Field2, Kavita Shah3, Friedhelm Bladt4, Tony Pawson4, Masaru Niki5, Pier Paolo Pandolfi5, Jean Y.J. Wang6, and Tony Hunter1

1 Molecular and Cell Biology Laboratory, The Salk Institute for Biological Sciences, La Jolla, CA 92037
2 Department of Pharmacology, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
3 Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121
4 Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada, M5G 1X5
5 Cancer Biology and Genetics Program, Department of Pathology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021
6 Division of Biological Sciences, Cancer Center, University of California, San Diego, La Jolla, CA 92093

Address correspondence to T. Hunter, Molecular and Cell Biology Laboratory, The Salk Institute for Biological Sciences, 10010 North Torrey Pines Rd., La Jolla, CA 92037-1099. Tel.: (858) 453-4100, ext. 1385. Fax: (858) 457-4765. email: hunter{at}salk.edu

Filopodia are dynamic F-actin structures that cells use to explore their environment. c-Abl tyrosine kinase promotes filopodia during cell spreading through an unknown mechanism that does not require Cdc42 activity. Using an unbiased approach, we identified Dok1 as a specific c-Abl substrate in spreading fibroblasts. When activated by cell adhesion, c-Abl phosphorylates Y361 of Dok1, promoting its association with the Src homology 2 domain (SH2)/SH3 adaptor protein Nck. Each signaling component was critical for filopodia formation during cell spreading, as evidenced by the finding that mouse fibroblasts lacking c-Abl, Dok1, or Nck had fewer filopodia than cells reexpressing the product of the disrupted gene. Dok1 and c-Abl stimulated filopodia in a mutually interdependent manner, indicating that they function in the same signaling pathway. Dok1 and c-Abl were both detected in filopodia of spreading cells, and therefore may act locally to modulate actin. Our data suggest a novel pathway by which c-Abl transduces signals to the actin cytoskeleton through phosphorylating Dok1 Y361 and recruiting Nck.

Key Words: Abl–/–Arg–/– fibroblasts; fibronectin adhesion; F-actin microspikes; cytoskeleton; Nck

The online version of this article includes supplemental material.

Abbreviations used in this paper: FN, fibronectin; KD, kinase-deficient; MEF, mouse embryo fibroblast; PH, pleckstrin homology; pTyr, phosphotyrosine; SH2, Src homology 2 domain; STI, signal transduction inhibitor; TLC, thin layer cellulose; WT, wild-type.


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