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 Streblow, Dusko Ilic, Mark H. Ginsberg, David D. Schlaepfer

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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 2005

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Focal Adhesion Protein-Tyrosine Kinases
Integrins
Cell Movement
Paxillin
Fibroblasts
Phosphorylation
Null Lymphocytes
Protein Tyrosine Phosphatases
GTP Phosphohydrolases
Fibronectins
Tyrosine

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Hsia, D. A., Lim, S. T., Bernard-Trifilo, J. A., Mitra, S. K., Tanaka, S., Den Hertog, J., ... 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

Integrin α4β1 promotes focal adhesion kinase-independent cell motility via α4 cytoplasmic domain-specific activation of c-Src. / Hsia, Datsun A.; Lim, Ssang Taek; Bernard-Trifilo, Joie A.; Mitra, Satyajit K.; Tanaka, Sakae; Den Hertog, Jeroen; Streblow, Daniel; Ilic, Dusko; Ginsberg, Mark H.; Schlaepfer, David D.

In: Molecular and Cellular Biology, Vol. 25, No. 21, 11.2005, p. 9700-9712.

Research output: Contribution to journalArticle

Hsia, DA, Lim, ST, Bernard-Trifilo, JA, Mitra, SK, Tanaka, S, Den Hertog, J, Streblow, D, Ilic, D, Ginsberg, MH & Schlaepfer, DD 2005, 'Integrin α4β1 promotes focal adhesion kinase-independent cell motility via α4 cytoplasmic domain-specific activation of c-Src', Molecular and Cellular Biology, vol. 25, no. 21, pp. 9700-9712. https://doi.org/10.1128/MCB.25.21.9700-9712.2005
Hsia, Datsun A. ; Lim, Ssang Taek ; Bernard-Trifilo, Joie A. ; Mitra, Satyajit K. ; Tanaka, Sakae ; Den Hertog, Jeroen ; Streblow, Daniel ; Ilic, Dusko ; Ginsberg, Mark H. ; Schlaepfer, David D. / Integrin α4β1 promotes focal adhesion kinase-independent cell motility via α4 cytoplasmic domain-specific activation of c-Src. In: Molecular and Cellular Biology. 2005 ; Vol. 25, No. 21. pp. 9700-9712.
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AU - Den Hertog, Jeroen

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