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HGF-promoted motility in primary human melanocytes depends on CD44v6 regulated via NF-kappa B, Egr-1, and C/EBP-beta.

ABSTRACT: The regulation of CD44v6, a variant of the CD44 family of glycosylated adhesion molecules, through hepatocyte growth factor (HGF) has implications for motility in primary human melanocytes. We show that exposure of primary human melanocytes to HGF results in an increase of CD44v6 expression. Immunostaining of melanocytic lesions revealed low cytoplasmic positivity of CD44v6 in some nevi but high membranous expression in primary cutaneous melanomas, and cutaneous and lymph node metastases. HGF-dependent CD44v6 regulation in melanocytes is NF-kappaB dependent because BAY 11-7082, an inhibitor of NF-kappaB activation, but not interference with the mitogen-activated protein kinase or phosphatidylinositol 3-kinase cascade, antagonized HGF-induced CD44v6 expression. NF-kappaB-mediated transcriptional regulation of CD44v6 involves the transcription factors Egr-1 and CCAAT enhancer-binding protein-beta (C/EBP-beta). In gel shift assays, the initial binding of p100/p52 NF-kappaB, C/EBP-beta, and Egr-1 to the CD44 promoter experienced reshuffling toward increased affinity of C/EBP-beta after HGF stimulation. A blocking antibody to CD44v6 decreased HGF-induced c-Met phosphorylation as well as enhanced random- and site-directed migration. Our data show that HGF-induced motility in primary human melanocytes depends on c-Met-CD44v6 interaction, and that HGF-enhanced CD44v6 expression is required for motility and transcriptional upregulation of CD44v6, presumably mediated through a complex comprising NF-kappaB/C/EBP-beta and Egr-1.

SUBMITTER: Damm S

PROVIDER: S-EPMC2989942 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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HGF-promoted motility in primary human melanocytes depends on CD44v6 regulated via NF-kappa B, Egr-1, and C/EBP-beta.

Damm Sabine S Koefinger Petra P Stefan Martina M Wels Christian C Mehes Gabor G Richtig Erika E Kerl Helmut H Otte Marcus M Schaider Helmut H

The Journal of investigative dermatology 20100401 7

The regulation of CD44v6, a variant of the CD44 family of glycosylated adhesion molecules, through hepatocyte growth factor (HGF) has implications for motility in primary human melanocytes. We show that exposure of primary human melanocytes to HGF results in an increase of CD44v6 expression. Immunostaining of melanocytic lesions revealed low cytoplasmic positivity of CD44v6 in some nevi but high membranous expression in primary cutaneous melanomas, and cutaneous and lymph node metastases. HGF-de ...[more]

PMID: 20357818

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Project description:Collective cell migration plays a major role in embryonic morphogenesis, tissue remodeling, wound repair and cancer invasion. Despite many decades of extensive investigations, only few analytical tools have been developed to enhance the biological understanding of this important phenomenon. Here we present a novel quantitative approach to analyze long term kinetics of bright field time-lapse wound healing. Fully-automated spatiotemporal measures and visualization of cells' motility and implicit morphology were proven to be sound, repetitive and highly informative compared to single-cell tracking analysis. We study cellular collective migration induced by tyrosine kinase-growth factor signaling (Met-Hepatocyte Growth Factor/Scatter Factor (HGF/SF)). Our quantitative approach is applied to demonstrate that collective migration of the adenocarcinoma cell lines is characterized by simple morpho-kinetics. HGF/SF induces complex morpho-kinetic coordinated collective migration: cells at the front move faster and are more spread than those further away from the wound edge. As the wound heals, distant cells gradually accelerate and enhance spread and elongation -resembling the epithelial to mesenchymal transition (EMT), and then the cells become more spread and maintain higher velocity than cells located closer to the wound. Finally, upon wound closure, front cells halt, shrink and round up (resembling mesenchymal to epithelial transition (MET) phenotype) while distant cells undergo the same process gradually. Met inhibition experiments further validate that Met signaling dramatically alters the morpho-kinetic dynamics of the healing wound. Machine-learning classification was applied to demonstrate the generalization of our findings, revealing even subtle changes in motility patterns induced by Met-inhibition. It is concluded that activation of Met-signaling induces an elaborated model in which cells lead a coordinated increased motility along with gradual differentiation-based collective cell motility dynamics. Our quantitative phenotypes may guide future investigation on the molecular and cellular mechanisms of tyrosine kinase-induced coordinate cell motility and morphogenesis in metastasis.

Dataset Information

HGF-promoted motility in primary human melanocytes depends on CD44v6 regulated via NF-kappa B, Egr-1, and C/EBP-beta.

Publications

HGF-promoted motility in primary human melanocytes depends on CD44v6 regulated via NF-kappa B, Egr-1, and C/EBP-beta.

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