c-Abl phosphorylates Dok1 to promote filopodia during cell spreading

J Cell Biol. 2004 May 24;165(4):493-503. doi: 10.1083/jcb.200312171. Epub 2004 May 17.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actins / biosynthesis
  • Adaptor Proteins, Signal Transducing
  • Animals
  • Cell Adhesion / genetics
  • Cell Line, Transformed
  • Cell Movement / physiology*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / physiology*
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Mice
  • Oncogene Proteins / metabolism
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Phosphoproteins / physiology*
  • Phosphorylation
  • Protein Structure, Tertiary / genetics
  • Proto-Oncogene Proteins c-abl / genetics
  • Proto-Oncogene Proteins c-abl / metabolism
  • Proto-Oncogene Proteins c-abl / physiology*
  • Pseudopodia / enzymology
  • Pseudopodia / physiology*
  • Pseudopodia / ultrastructure
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • RNA-Binding Proteins / physiology*
  • Signal Transduction / genetics
  • src Homology Domains / physiology

Substances

  • Actins
  • Adaptor Proteins, Signal Transducing
  • DNA-Binding Proteins
  • Dok1 protein, mouse
  • GAP-associated protein p62
  • Nck protein
  • Oncogene Proteins
  • Phosphoproteins
  • RNA-Binding Proteins
  • Proto-Oncogene Proteins c-abl