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.

c-Abl phosphorylates Dok1 to promote filopodia during cell spreading.

PANDOLFI DE RINALDIS, Pier Paolo;
2004-01-01

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.
2004
165
493
503
http://dx.doi.org/10.1083/jcb.200312171
Actins; Animals; Cell Adhesion; Cell Line; Transformed; Cell Movement; DNA-Binding Proteins; Fibroblasts; Mice; Oncogene Proteins; Phosphoproteins; Phosphorylation; Protein Structure; Tertiary; Proto-Oncogene Proteins c-abl; Pseudopodia; RNA-Binding Proteins; Signal Transduction; src Homology Domains
P. J. Woodring;J. Meisenhelder;S. A. Johnson;G. Zhou;J. Field;K. Shah;F. Bladt;T. Pawson;M. Niki;P. P. Pandolfi;J. Y. J Wang;T. Hunter
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/60980
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