Integrin α4β1 promotes focal adhesion kinase-independent cell motility via α4 cytoplasmic domain-specific activation of c-Src

Datsun A. Hsia, Ssang Taek Lim, Joie A. Bernard-Trifilo, Satyajit K. Mitra, Sakae Tanaka, Jeroen Den Hertog, Daniel N. Streblow, Dusko Ilic, Mark H. Ginsberg, David D. Schlaepfer

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

The fibronectin binding integrins α5β1 and α4β1 generate signals pivotal for cell migration through distinct yet undefined mechanisms. For α5β1, β1-mediated activation of focal adhesion kinase (FAK) promotes c-Src recruitment to FAK and the formation of a FAK-Src signaling complex. Herein, we show that FAK expression is essential for α5β1-stimulated cell motility and that exogenous expression of human α4 in FAK-null fibroblasts forms a functional α4β1 receptor that promotes robust cell motility equal to the α5β1 stimulation of wild-type and FAK-reconstituted fibroblasts. α4β1-stimulated FAK-null cell spreading and motility were dependent on the integrity of the α4 cytoplasmic domain, independent of direct paxillin binding to α4, and were not affected by PRNK expression, a dominant-negative inhibitor of Pyk2. α4 cytoplasmic domain-initiated signaling led to a ∼4-fold activation of c-Src which did not require paxillin binding to α4. Notably, α4-stimulated cell motility was inhibited by catalytically inactive receptor protein-tyrosine phosphatase α over-expression and blocked by the p50Csk phosphorylation of c-Src at Tyr-529. α4β1-stimulated cell motility of triple-null Src-/-, c-Yes-/-, and Fyn -/- fibroblasts was dependent on c-Src reexpression that resulted in p130Cas tyrosine phosphorylation and Rac GTPase loading. As p130Cas phosphorylation and Rac activation are common downstream targets for α5β1-stimulated FAK activation, our results support the existence of a novel α4 cytoplasmic domain connection leading to c-Src activation which functions as a FAK-independent linkage to a common motility-promoting signaling pathway.

Original languageEnglish (US)
Pages (from-to)9700-9712
Number of pages13
JournalMolecular and cellular biology
Volume25
Issue number21
DOIs
StatePublished - Nov 1 2005

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Hsia, D. A., Lim, S. T., Bernard-Trifilo, J. A., Mitra, S. K., Tanaka, S., Den Hertog, J., Streblow, D. N., Ilic, D., Ginsberg, M. H., & Schlaepfer, D. D. (2005). Integrin α4β1 promotes focal adhesion kinase-independent cell motility via α4 cytoplasmic domain-specific activation of c-Src. Molecular and cellular biology, 25(21), 9700-9712. https://doi.org/10.1128/MCB.25.21.9700-9712.2005