c-Abl phosphorylates Dok1 to promote filopodia during cell spreading.
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.
Woodring
Pamela J
PJ
Molecular and Cell Biology Laboratory, The Salk Institute for Biological Sciences, 10010 North Torrey Pines Rd., La Jolla, CA 92037-1099, USA.
Meisenhelder
Jill
J
Johnson
Sam A
SA
Zhou
Guo-Lei
GL
Field
Jeffrey
J
Shah
Kavita
K
Bladt
Friedhelm
F
Pawson
Tony
T
Niki
Masaru
M
Pandolfi
Pier Paolo
PP
Wang
Jean Y J
JY
Hunter
Tony
T
D000199:Actins / Q000096:biosynthesis; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002448:Cell Adhesion / Q000235:genetics; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D051379:Mice; D015513:Oncogene Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary / Q000235:genetics; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011554:Pseudopodia / Q000201:enzymology / Q000502:physiology* / Q000648:ultrastructure; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics; D018909:src Homology Domains / Q000502:physiology
D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C489561:Dok1 protein, mouse; C074561:GAP-associated protein p62; C078332:Nck protein; D015513:Oncogene Proteins; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D016315:Proto-Oncogene Proteins c-abl