Caveolin-1-dependent β1 integrin endocytosis is a critical regulator of fibronectin turnover

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Abstract
β1 integrins are major cell surface receptors for fibronectin. Some integrins, including β1 integrins, are known to undergo constitutive endocytosis and recycling. Integrin endocytosis/recycling has been implicated in the regulation of cell migration. However, the mechanisms by which integrin endocytosis/recycling regulates cell migration, and other biological consequences of integrin trafficking are not completely understood. We previously showed that turnover of extracellular matrix (ECM) fibronectin occurs via receptor-mediated endocytosis. Here, we investigate the biological relevance of β1 integrin endocytosis to fibronectin matrix turnover. First, we demonstrate that β1 integrins, including α5β1 play an important role in endocytosis and turnover of matrix fibronectin. Second, we show that caveolin-1 constitutively regulates endocytosis of α5β1 integrins, and that α5β1 integrin endocytosis can occur in the absence of fibronectin and fibronectin matrix. We also show that downregulation of caveolin-1 expression by siRNA results in marked reduction of β1 integrin and fibronectin endocytosis. Hence, caveolin-1-dependent β1 integrin and fibronectin endocytosis plays a critical role in fibronectin matrix turnover, and may contribute to abnormal ECM remodeling that occurs in fibrotic disorders.