Cells that are anchorage-dependent, requiring attachment to a substrate to survive, exhibit signaling through multiple pathways, and this signaling is disrupted when the cells are detached from the substrate. del Pozo et al. suggest that redistribution of phosphorylated caveolin-1 (Cav1) from focal adhesions to the plasma membrane promotes the internalization of cholesterol-enriched membrane microdomains (CEMM), including caveolae, and that this is necessary for inhibition of signaling pathways that are active in anchored cells. Suspended cells (NIH-3T3) exhibited loss of cell surface ganglioside GM1, a marker of CEMM; loss of caveolae from the cell surface; and redistribution of Cav1 to intracellular compartments. In Cav1-deficient cells, such as M21L melanoma cells or Cav1—/—mouse embryo fibroblasts (MEFs), GM1 remained at the cell surface in suspended cells; in the M21L cells, a tagged version of the guanosine triphosphatase Rac also remained associated with the plasma membrane and active in detached cells. Phosphorylated Cav1 appeared to be required to rescue the internalization-deficient phenotype, because transfection of the Cav1-deficient cells with a caveolin mutant that could not be phosphorylated did not restore internalization of CEMM. In attached NIH-3T3 cells or MEFs, phosphorylated Cav1 represented a small fraction of total Cav1 but was localized to focal adhesion sites. In detached cells, phosphorylated Cav1 was dispersed throughout the plasma membrane. In addition to being required for CEMM internalization upon cell detachment, Cav1 was required for the inhibition of phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and Akt and the inhibition of the kinase Pak. Thus, the authors suggest that Cav1-mediated internalization of CEMM is a mechanism for adhesion-dependent regulation of signaling pathways important for cell survival of attached cells. Furthermore, they propose that loss of this process in Cav1-deficient cells may contribute to cancer and tumorigenesis by disconnecting integrin-mediated attachment signals from the signaling pathways that control cell survival.
M. A. del Pozo, N. Balasubramanian, N. B. Alderson, W. B. Kiosses, A. Grande-Garcia, R. G. W. Anderson, M. A. Schwartz, Phospho-caveolin-1 mediates integrin-regulated membrane domain internalization. Nat. Cell Biol. 7, 901-908 (2005). [PubMed]