Caveolin-1 regulates cell polarization and directional migration through Src kinase and Rho GTPases

Abstract

Development, angiogenesis, wound healing, and metastasis all involve the movement of cells in response to changes in the extracellular environment. To determine whether caveolin-1 plays a role in cell migration, we have used fibroblasts from knockout mice. Caveolin-1–deficient cells lose normal cell polarity, exhibit impaired wound healing, and have decreased Rho and increased Rac and Cdc42 GTPase activities. Directional persistency of migration is lost, and the cells show an impaired response to external directional stimuli. Both Src inactivation and p190RhoGAP knockdown restore the wild-type phenotype to caveolin-1–deficient cells, suggesting that caveolin-1 stimulates normal Rho GTP loading through inactivation of the Src–p190RhoGAP pathway. These findings highlight the importance of caveolin-1 in the establishment of cell polarity during directional migration through coordination of the signaling of Src kinase and Rho GTPases.

Lipid Rafts and Caveolae in Signaling by Growth Factor Receptors

“…Nevins and Thurmond demonstrated the interaction between caveolin-1 and Cdc42 [50]. Further studies also revealed a role in the activation and regulation of Rho, suggesting a role of caveolin-1 in cell polarity and migration [51]. del Pozo et al [52] reported that lipid rafts are involved in signal transduction events initiated by cell adhesion to the extracellular matrix, which is mediated by integrins.…”

Bidirectional control of the inner dynamics of focal adhesions promotes cell migration

“…8 Cav1 Y14 has also been shown to promote cell polarization and directional migration in mouse embryonic fibroblasts by enabling Src-mediated RhoGTPase activity. 39 More recently, we showed that tyrosine-phosphorylated Cav1 functions as an effector of Rho/ROCK signaling in the regulation of FA turnover, defining a feedback loop between Rho/ROCK, Src and phosphorylated Cav1 in tumor cell migration. 41 …”

“…40 Gal-3-mediated integrin activation therefore acts through pY14Cav1 to induce a membrane organization within FA that restricts exchange of FAK and other FA components and enables FA turnover. In two additional studies, pY14Cav1 has been shown to recruit Csk, thereby inhibiting Src activity and leading to a p190RhoGAP-dependent increase in RhoGTP levels; 39 this regulates the localization of pY14Cav1 to cell protrusions as well as the dynamics of FAK at focal adhesion sites, and thus influences tumor cell migration. 41 Thus, pY14Cav1 sufficiently stabilizes FA components at FA sites to allow FA maturation, substrate adherence at cellular protrusions, and directional motility.…”

“…37 Downregulation of Cav1 results in decreases of focal adhesion number, cell polarization and directional cell movement. 38,39 Phosphorylation of Cav1 on tyrosine 14 regulates domain recruitment of various signaling adapters, such as kinases and phosphatases, suggesting that Cav1 signaling activity might be equally as important as its structural role in caveolae formation. Indeed, Cav1, in particular its tyrosine phosphorylated form, regulates and stabilizes FAK exchange in focal adhesions, enabling FA-mediated signaling and cell migration in tumor cell lines.…”

Lipid Rafts and Caveolae in the Terminal Differentiation of Epidermal Keratinocytes

“…Cav-1 possesses a 'scaffolding domain' that interacts with signal transduction molecules [11]. Not only is this domain required to form multivalent homo-oligomers with other cav proteins, but it also mediates the interaction of cav-1 with non-cav proteins, such as the G-subunits, Ha-Ras, Src family kinases and eNOS [12][13][14][15]. Consequently, cav-1 acts as molecular 'Velcro' where signal transduction complexes are bound in the inactivated state [16].…”