Role of N-cadherin and beta-catenin signaling during transendothelial migration of melanoma cells.
Published: 2006
Language: eng
Number of pages: 240
ISBN-13: 9780494217740
Description: Cancer metastasis is a multi-step process involving many types of cell-cell interactions, but little is known about the molecular mechanisms underlying extravasation of cancer cells. To investigate transendothelial migration (TEM) of cancer cells, our laboratory has developed an in vitro co-culture assay, in which melanoma cells are seeded on top of a monolayer of lung microvascular endothelial cells. N-cadherin was recruited to the heterotypic contact between transmigrating melanoma cells and neighboring endothelial cells, whereas beta-catenin was found to dissociate from N-cadherin and redistribute to the nucleus of melanoma cells to activate gene transcription. TEM of melanoma cells was inhibited when N-cadherin expression or beta-catenin signaling was repressed in melanoma cells, indicating a key role played by N-cadherin and beta-catenin signaling. Further studies indicate that Src was activated at the heterotypic contact, and this led to tyrosine phosphorylation of N-cadherin at Tyr860, which disrupted beta-catenin binding. Src also activated the MAPK-ERK pathway to stabilize the dissociated beta-catenin, thereby leading to the activation of beta-catenin signaling. Finally, I found that N-cadherin became associated with lipid rafts/caveolae during TEM of melanoma cells. This is a prerequisite for tyrosine phosphorylation of N-cadherin by Src, which may also provide a potential mechanism whereby the N-cadherin adhesion complex is stabilized in the absence of beta-catenin-mediated cytoskeletal connection. Taken together, these results elucidate a novel mechanists for N-cadherin-mediated adhesion and signaling events that promote TEM of melanoma cells.
Notes: Source: Dissertation Abstracts International, Volume: 68-01, Section: B, page: 0043.

Thesis (Ph.D.)--University of Toronto, 2006.

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