Met Receptor Subcellular Localization Depends on E-Cadherin Function

Abstract

Overexpression of the HGF (hepatocyte growth factor) receptor Met is correlated with metastasis and poor outcome in cancer. Upon HGF binding, Met mediates multiple cellular processes, including mitogenesis, motility, and morphogenesis[1]. Met and HGF likely play a key role in regulating many aspects of embryonic development, including epithelial-mesenchymal transition[2], migration of muscle cells[3], and kidney and mammary gland formation[4,5]. Met signaling also facilitates wound healing and tissue regeneration[6]. Met oncogenic activation was shown to play a significant role in promoting tumor cell invasion and metastasis[7]. In vitro, activation of Met by HGF induces disassembly of the cell-cell contacts, followed by cell migration[8]. E-cadherin is the central protein of adhesion complexes in epithelial cells. E-cadherin is a transmembrane protein whose cytoplasmic domains interact with catenins to connect to the cytoskeleton[9]. However, the mechanism involved in down-regulation of E-cadherin function by Met is poorly understood. One important question that has not been resolved is whether E-cadherin and Met have physically interacted at the plasma membrane. There are only a few data suggesting that Met might tightly interact with the E-cadherin-dependent adhesion complex. Met has been shown to be selectively localized at the basolateral area of polarized epithelial cells in vivo[10]. Also, Met and E-cadherin were found colocalized on the membrane of human carcinoma cells in vitro[11,12]. Moreover, in MDCK cells, both proteins were colocalized at the cell-cell adhesion site and underwent coendocytosis upon HGF stimulation[13]. We have now shown that Met is tightly associated with E-cadherin at the site of cell-cell contacts[14]. It appears that the interaction of Met and E-cadherin occurs by direct binding in their extracellular domains as part of the process of maturation of adhesive junctions. The cadherin-mediated cell adhesion divided the plasma membrane into apical and basolateral domains that have different protein compositions[15]. Recently, new data concerning the dynamics of plasma membrane proteins in epithelial cells were published. It was demonstrated that proteins that are normally localized at the plasma membrane in polarized epithelial cells distributed to intacellular compartments when cell polarity is lost or not yet established because of redirection of plasma membrane transport pathways into intracellular vesicles[16,17]. Interestingly, such membrane markers like E-cadherin, β-catenin, occludin, JAM-1, Na/K-ATPase, and syntaxins were accumulated in the unique intracellular storage compartment upon destruction of cell-cell adhesion[18]. Our work demonstrated that E-cadherin-negative BT-549 cells delivered Met to an intracellular location. However, forced expression of E-cadherin restored cell-cell contacts and recruited Met to the membrane.

The clinical and functional significance of c-Met in breast cancer: a review

“…Numerous studies have sought to uncover the mechanisms through which HGF/c-Met signalling contributes to the migratory and invasive phenotype in breast cancer, particularly focusing on pathways associated with epithelial adhesion [ 65 - 67 ]. E-Cadherin is a key component of adherens junctions (specialised intraepithelial junctions) [ 68 , 69 ], and is regarded by some as a tumour suppressor important in the prevention of cell migration, invasion and metastasis [ 69 ].…”