Has HGF met other partners? Met-independent epithelial morphogenesis induced by HGF. Focus on “Hepatocyte growth factor induces MDCK cell morphogenesis without causing loss of tight junction functional integrity”

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Abstract
Polarized epithelial cells line the majority of vertebrate organs (including the urinary, digestive, and respiratory tracts), where they are responsible for life-sustaining vectorial transport and barrier functions. Morphogenesis of the epithelial cell phenotype is a complex phenomenon, and several decades of pioneering multidisciplinary studies have now begun to yield important clues toward our understanding of this process. Developmental and molecular biological investigations have identified critical growth and transcription factors that direct the biogenesis of epithelial organs. Concurrently, cell biological studies of epithelia cultured on two-dimensional filter supports or within three-dimensional extracellular matrix (ECM) systems have provided us with novel insights into the mechanisms by which these factors orchestrate epithelial morphogenesis. These approaches have recently led to the proposal of a two-phase working hypothesis ([8][1], [12][2]). The first phase entails the conversion of single cells into a polarized monolayer, regulated primarily by an intrinsic genetically determined program. This is initiated in filter-supported systems by the establishment of cell-cell contact, which serves as a cue for the recruitment of adherens junction molecules (such as E-cadherin) and proteins of the tight junction (such as ZO-1). The ensuing cytoskeletal rearrangements ([10][3]), and selective sorting of plasma membrane proteins to the apical or basolateral domains as demarcated by tight junctions ([9][4]), complete the generation of a polarized epithelium. In three-dimensional systems, the first phase begins with several rounds of cell division. Daughter cells display lateral membrane domains containing adherens and tight junctions at sites of cell-cell contact and basal domains containing integrin-receptor complexes at sites of cell-ECM contact. Elaboration and assembly of laminin at the basal surface provide a cue for lumen formation and generation of apical domains. Cells devoid of ECM contact undergo programmed cell death, resulting in luminal expansion and generation of a mature cyst. The second phase of epithelial morphogenesis results in remodeling of the polarized monolayer and includes processes such as branching morphogenesis ([23][5]), tubulogenesis ([16][6]), and pseudostratification ([14][7]). This phase is regulated by extrinsic factors, the most prominent being hepatocyte growth factor (HGF), which is the focus of this review. HGF was originally identified as a mitogen for hepatocytes and subsequently shown to be identical to scatter factor (SF), a fibroblast-derived ligand that possesses a distinct property of inducing epithelial cell dissociation. Increasing evidence now suggests that HGF is a multifunctional molecule that exerts a plethora of effects on epithelial cells, including mitogenesis, motogenesis, morphogenesis, tubulogenesis, induction of cell polarity, inhibition of apoptosis, and promotion of invasiveness ([6][8], [16][6], [23][5]). HGF is a heterodimeric molecule that is biosynthesized and secreted as an inactive precursor by cells of mesodermal origin in mature (fibroblasts, monocytes, platelets) and developing (placenta, liver, kidney) humans. Conversion to the active form requires proteolytic processing by extracellular activators such as urokinase-type plasminogen activator and HGF-specific serine protease. The high-affinity receptor for HGF is the receptor tyrosine kinase c-Met, and all of the pleiotropic cellular consequences of HGF activation are thought to be transduced via Met ([3][9], [16][6], [23][5]). Met is expressed in virtually all epithelial cells and is markedly induced in a variety of human epithelial tumor cells ([17][10]). The essential role of HGF and Met during mammalian development has been documented by targeted deletion of either of these genes in mice, which resulted in embryonic lethality due to impaired organogenesis of the placenta and liver. Binding of HGF to Met induces receptor dimerization and autophosphorylation at a conserved two-tyrosine motif within the receptor docking site ([3][9]). The significance of this is underscored by the finding that mice harboring mutations at the tyrosine residues display the same phenotype as the HGF or Met knockouts. Met activation results in the recruitment of a growing array of intertwined downstream signal transduction molecules that are the subjects of intense current research ([3][9], [16][6], [17][10], [23][5]). Mounting evidence suggests an intriguing specificity of phenotypic readout depending on the intracellular pathway that is activated ([3][9]). Madin-Darby canine kidney (MDCK) cell culture models have been instrumental in elucidating the role of HGF in epithelial morphogenesis. First, single cells or small colonies grown on impermeant supports become motile and scatter away when exposed to HGF, providing a useful model for HGF-induced tumor invasion and metastasis. Second, cells grown as cysts within ECM systems respond to HGF by forming complex branching tubules. This system has been studied extensively as a model of branching morphogenesis that occurs during normal development of epithelial organs such as the kidneys and lungs. Third, MDCK cells grown to confluence on permeable filter supports form fully polarized monolayers with morphologically and functionally distinct apical and basolateral membrane domains separated by a continuous tight junction belt. Met is localized to the basolateral cell surface, and cells respond to basolateral but not apical HGF. This system has proved particularly relevant to the study of alterations in cell polarity commonly associated with acute injuries of epithelial organs. HGF induces confluent monolayers of MDCK cells to undergo pseudostratification, a response that requires an increase in monolayer thickness, an increase in tortuosity of lateral membranes, and the extension and crawling of cells over each other ([2][11]). The...

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