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Loss of beta1-integrin enhances TGF-beta1-induced collagen expression in epithelial cells via increased alphavbeta3-integrin and Rac1 activity.


ABSTRACT: Transforming growth factor ? (TGF-?) promotes tissue fibrosis via the receptor-specific Smad pathway and non-canonical pathways. We recently reported that TGF-?1-stimulated collagen expression by cultured kidney cells requires integrin-dependent activation of focal adhesion kinase (FAK) and consequent ERK MAP kinase activity leading to Smad3 linker region phosphorylation. Here, we defined a role for ?v?3-integrin in this non-canonical pathway. A human kidney tubular cell line in which ?1-integrin was knocked down (?1-k/d) demonstrated enhanced type I collagen mRNA expression and promoter activity. A second shRNA to either ?v-integrin or ?3-integrin, but not to another ?v-binding partner, ?6-integrin, abrogated the enhanced COL1A2 promoter activity in ?1-k/d cells. Although ?v?3-integrin surface expression levels were not different, ?v?3-integrins colocalized with sites of focal adhesion significantly more in ?1-k/d cells, and activated ?v?3-integrin was detected only in ?1-k/d cells. Further, the collagen response was decreased by a function-blocking antibody or a peptide inhibitor of ?v?3-integrin. In cells lacking ?v?3-integrin, the responses were attenuated, whereas the response was enhanced in ?v?3-overexpressing cells. Rac1 and ERK, previously defined mediators for this non-canonical pathway, showed increased activities in ?1-k/d cells. Finally, inhibition of ?v?3-integrin decreased Rac1 activity and COL1A2 promoter activity in ?1-k/d cells. Together, our results indicate that decreasing ?1 chain causes ?v?3-integrin to become functionally dominant and promotes renal cell fibrogenesis via Rac1-mediated ERK activity.

SUBMITTER: Hayashida T 

PROVIDER: S-EPMC2945568 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Loss of beta1-integrin enhances TGF-beta1-induced collagen expression in epithelial cells via increased alphavbeta3-integrin and Rac1 activity.

Hayashida Tomoko T   Jones Jonathan C R JC   Lee Carrie K CK   Schnaper H William HW  

The Journal of biological chemistry 20100722 40


Transforming growth factor β (TGF-β) promotes tissue fibrosis via the receptor-specific Smad pathway and non-canonical pathways. We recently reported that TGF-β1-stimulated collagen expression by cultured kidney cells requires integrin-dependent activation of focal adhesion kinase (FAK) and consequent ERK MAP kinase activity leading to Smad3 linker region phosphorylation. Here, we defined a role for αvβ3-integrin in this non-canonical pathway. A human kidney tubular cell line in which β1-integri  ...[more]

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