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Vol. 20, Issue 19, 4140-4152, October 1, 2009

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

Lidiya Orlichenko^*,, Shaun G. Weller^*,, Hong Cao^*, Eugene W. Krueger^*, Muyiwa Awoniyi^*, Galina Beznoussenko, Roberto Buccione, and Mark A. McNiven^*

*Mayo Clinic, Department of Biochemistry and Molecular Biology and the Miles and Shirley Fiterman Center for Digestive Diseases, Rochester, MN 55905; and Consorzio Mario Negri Sud, Santa Maria Imbaro (Chieti) 66030, Italy

Submitted October 17, 2008; Revised July 6, 2009; Accepted July 22, 2009
Monitoring Editor: Keith E. Mostov

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.

These authors contributed equally to this work.

Address correspondence to: Mark A. McNiven (mcniven.mark{at}mayo.edu).

Abbreviations used: AJ, adherens junction; Cav1, caveolin-1; E-cad, E-cadherin; PM, plasma membrane; siRNA, small interfering RNA; TER, transepithelial electrical resistance.