Journal
JOURNAL OF CELL BIOLOGY
Volume 180, Issue 1, Pages 187-203Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200708194
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Funding
- NCI NIH HHS [CA87038, R01 CA075240, R29 CA075240, R01 CA087038, R01 CA102310, CA102310, CA75240] Funding Source: Medline
- NIGMS NIH HHS [R01 GM067230, U01 GM067230, GM67230] Funding Source: Medline
- NINDS NIH HHS [NS515722] Funding Source: Medline
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Integrin binding to matrix proteins such as fibronectin (FN) leads to formation of focal adhesion (FA) cellular contact sites that regulate migration. RhoA GTPases facilitate FA formation, yet FA-associated RhoA-specific guanine nucleotide exchange factors (GEFs) remain unknown. Here, we show that proline-rich kinase-2 (Pyk2) levels increase upon loss of focal adhesion kinase (FAK) in mouse embryonic fibroblasts (MEFs). Additionally, we demonstrate that Pyk2 facilitates deregulated RhoA activation, elevated FA formation, and enhanced cell proliferation by promoting p190RhoGEF expression. In normal MEFs, p190RhoGEF knockdown inhibits FN-associated RhoA activation, FA formation, and cell migration. Knockdown of p190RhoGEF-related GEFH1 does not affect FA formation in FAK(-/-) or normal MEFs. p190RhoGEF overexpression enhances RhoA activation and FA formation in MEFs dependent on FAK binding and associated with p190RhoGEF FA recruitment and tyrosine phosphorylation. These studies elucidate a compensatory function for Pyk2 upon FAK loss and identify the FAK-p190RhoGEF complex as an important integrin-proximal regulator of FA formation during FN-stimulated cell motility.
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