Caveolae Mediate Growth Factor-induced Disassembly of Adherens Junctions to Support Tumor Cell Dissociation

Mayo Clinic, Department of Biochemistry and Molecular Biology and the Miles and Shirley Fiterman Center for Digestive Diseases, Rochester, MN 55905, USA.
Molecular biology of the cell (Impact Factor: 5.98). 08/2009; 20(19):4140-52. DOI: 10.1091/mbc.E08-10-1043
Source: PubMed

ABSTRACT Remodeling of cell-cell contacts through the internalization of adherens junction proteins is an important event during both normal development and the process of tumor cell metastasis. Here we show that the integrity of tumor cell-cell contacts is disrupted after epidermal growth factor (EGF) stimulation through caveolae-mediated endocytosis of the adherens junction protein E-cadherin. Caveolin-1 and E-cadherin closely associated at cell borders and in internalized structures upon stimulation with EGF. Furthermore, preventing caveolae assembly through reduction of caveolin-1 protein or expression of a caveolin-1 tyrosine phospho-mutant resulted in the accumulation of E-cadherin at cell borders and the formation of tightly adherent cells. Most striking was the fact that exogenous expression of caveolin-1 in tumor cells that contain tight, well-defined, borders resulted in a dramatic dispersal of these cells. Together, these findings provide new insights into how cells might disassemble cell-cell contacts to help mediate the remodeling of adherens junctions, and tumor cell metastasis and invasion.

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    • "A wealth of recent evidence points to a crucial role of E-cadherin endocytosis and recycling in tissue morphogenesis and EMT (Baum and Georgiou, 2011). Endocytic removal of E-cadherin from the cell surface is acutely induced by activation of receptor (Orlichenko et al., 2009) and nonreceptor (Avizienyte et al., 2002) tyrosine kinases, as well as by stimulation with transforming growth factor-b (TGF-b) (Janda et al., 2006). In the case of epidermal growth factor (EGF)-induced E-cadherin downregulation and AJ disassembly, SRC has an important role. "
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    • "We have not distinguished these pathways, since they all recruit Rab5 for endosome formation. While published evidence indicates that a caveolin-1-associated pathway may mediate EGF-induced E-cad internalization (Lu et al., 2003; Orlichenko et al., 2009; Masuelli et al., 2012), our finding that the E-cad/ b-catenin complex is maintained in endocytic vesicles differs from reports on cancer cells lines, in which EGF overexpression induces E-cad endocytosis and disassembly of b-catenin from E-cad-catenin complex in a caveolin-1-associated pathway (Lu et al., 2003). Hakai was shown to control E-cad endocytosis via clathrin-coated vesicles, marking it for degradation (Fujita et al., 2002). "
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    • "However, in other studies it was reported to reduce tumorigenesis and lung metastasis of HNSCC (Zhang et al., 2008). EGF stimulation of pancreatic cancer cells induces an increased association of caveolin-1 with E-cadherin in the course of disassembly of cell junctions (Orlichenko et al., 2009). We previously Fig. 4. Co-localization of b-catenin, EGFR, and caveolin-1 in unstimulated and EGF-stimulated FaDu cells. "
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