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: 4.47). 08/2009; 20(19):4140-52. DOI: 10.1091/mbc.E08-10-1043
Source: PubMed


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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Available from: Galina V Beznoussenko, May 21, 2015
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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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    • "For example, vascular endothelial growth factor (VEGF)-induced vascular hyperpermeability and the internalization of VE-cad is clathrin-mediated [14]. Some evidence suggests that the internalization of epithelial cadherin (E-cad) could also occur via clathrin-independent, caveolae-mediated pathways in some epithelial tumor cell types, which contributes to the disassembly of AJs and tumor cell invasion [15], [16]. However, it is unknown whether the clathrin-mediated endocytosis of VE-cad and/or the caveolae-mediated endocytosis of VE-cad also contribute to LPS-induced vascular hyperpermeability, whether they contribute in similar or different manners, and which mechanisms might be relevant in these processes. "
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