c-Abl phosphorylates Dok1 to promote filopodia during cell spreading

Author:

Woodring Pamela J.1,Meisenhelder Jill1,Johnson Sam A.1,Zhou Guo-Lei2,Field Jeffrey2,Shah Kavita3,Bladt Friedhelm4,Pawson Tony4,Niki Masaru5,Pandolfi Pier Paolo5,Wang Jean Y.J.6,Hunter Tony1

Affiliation:

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

Abstract

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.

Publisher

Rockefeller University Press

Subject

Cell Biology

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