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

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. INTRODUCTIONPolarized epithelial cells such as those in ductular organs, including the pancreas, form and maintain their tubular tissue architecture through regulated associations with adjacent cells (Hogan and Kolodziej, 2002;Lubarsky and Krasnow, 2003;Zegers et al., 2003). The integrity of these lateral interactions is mediated, in part, by adherens junctions (AJs), of which the transmembrane protein E-cadherin (E-cad) is a major component. On the extracellular side, homophilic antiparallel interactions between E-cad molecules present on adjacent cells mediate the assembly and maintenance of AJs, whereas on the intracellular side the cytoplasmic tail of E-cad is associated with an array of actin cytoskeletal proteins as well as signaling molecules such as catenins, small GTPases, and nonreceptor tyrosine kinases (Perez-Moreno et al., 2003;Gumbiner, 2005). Although maintenance of stable junctions is important for tissue integrity and the functional properties of polarized epithelia, AJs are also dynamic structures undergoing cycles of assembly and disassembly. Indeed, reorganization of AJs is a key aspect of tissue morphogenesis both during normal development as well as tumor cell metastasis, when the structural integrity of AJs is compromised as tumor cells lose polarity and subsequently dissociate before migration (Thiery, 2002;Cavallaro and Christofori, 2004).Pancreatic cancer is a particularly deadly disease and is listed as one of the top five most lethal cancers in the United States (Jemal et al., 2006). Although less prevalent than other cancers, its mortality rate is well over 90% within 6 mo of diagnosis. This exceptionally high lethality is due to a lack of early diagnostic tools, the dispersed organization of the pancreas within the abdomen, and a significant propensity of neoplastic cells to disseminate and migrate from the pancreas to nearby organs (Shi et al., 2001;Freelove and Walling, 2006).A reduction ...

Regulation of Caveolin-1 and Junction Proteins by bFGF Contributes to the Integrity of Blood–Spinal Cord Barrier and Functional Recovery

“…A recent study has illustrated that Cav-1 mediated growth factor-induced disassembly of adherens junctions to support tumor cell dissociation [46]. In the blood-tumor barrier, Cav-1 also participates in VEGF-mediated permeability [47].…”

Intestine-specific transcription factor Cdx2 induces E-cadherin function by enhancing the trafficking of E-cadherin to the cell membrane

“…Caveolae are important modulators of a variety of cell surface receptors (30,36,38,47): they are required for signaling in some instances and silencing in others. Cellular and tissue context likely plays a role in these divergent effects.…”

“…Caveolae are specialized plasma membrane microdomains that have been implicated in a variety of physiological processes, including membrane trafficking, cell motility, and signal transduction (including RTKs) (30,36,38,47 (Fig. 11, A and B).…”

The regulation of cell-cell adhesion during epithelial-mesenchymal transition, motility and tumor progression

“…86 In cancer cells, EGF can induce caveolin-1-mediated degradation of Ecadherin and tumor cell dissociation. 87,88 Reggie/flotillins are microdomain scaffolding proteins (lipid raft components) that play an important role in Wnt and Shh signaling 89 and are involved in regulating membrane trafficking and turnover. 90,91 In association with prion protein (PrP), reggies/ flotillins control activation of Src kinases and the presence of receptor tyrosine kinases such as EGFR at the membrane.…”