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EphA kinase activation regulates HGF-induced epithelial branching morphogenesis

Eph kinases and their ephrin ligands are widely expressed in epithelial cells in vitro and in vivo. Our results show that activation of endogenous EphA kinases in Madin-Darby canine kidney (MDCK) cells negatively regulates hepatocyte growth factor/scatter factor (HGF)–induced branching morphogenesis...

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Autores principales: Miao, Hui, Nickel, Christian H., Cantley, Lloyd G., Bruggeman, Leslie A., Bennardo, Laura N., Wang, Bingcheng
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2003
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2173949/
https://www.ncbi.nlm.nih.gov/pubmed/14517207
http://dx.doi.org/10.1083/jcb.200304018
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author Miao, Hui
Nickel, Christian H.
Cantley, Lloyd G.
Bruggeman, Leslie A.
Bennardo, Laura N.
Wang, Bingcheng
author_facet Miao, Hui
Nickel, Christian H.
Cantley, Lloyd G.
Bruggeman, Leslie A.
Bennardo, Laura N.
Wang, Bingcheng
author_sort Miao, Hui
collection PubMed
description Eph kinases and their ephrin ligands are widely expressed in epithelial cells in vitro and in vivo. Our results show that activation of endogenous EphA kinases in Madin-Darby canine kidney (MDCK) cells negatively regulates hepatocyte growth factor/scatter factor (HGF)–induced branching morphogenesis in collagen gel. Cotreatment with HGF and ephrin-A1 reduced sprouting of cell protrusions, an early step in branching morphogenesis. Moreover, addition of ephrin-A1 after HGF stimulation resulted in collapse and retraction of preexisting cell protrusions. In a newly developed assay that simulates the localized interactions between Ephs and ephrins in vivo, immobilized ephrin-A1 suppressed HGF-induced MDCK cell scattering. Ephrin-A1 inhibited basal ERK1/2 mitogen-activated protein kinase activity; however, the ephrin-A1 effect on cell protrusion was independent of the mitogen-activated protein kinase pathway. Ephrin-A1 suppressed HGF-induced activation of Rac1 and p21-activated kinase, whereas RhoA activation was retained, leading to the preservation of stress fibers. Moreover, dominant-negative RhoA or inhibitor of Rho-associated kinase (Y27632) substantially negated the inhibitory effects of ephrin-A1. These data suggest that interfering with c-Met signaling to Rho GTPases represents a major mechanism by which EphA kinase activation inhibits HGF-induced MDCK branching morphogenesis.
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spelling pubmed-21739492008-05-01 EphA kinase activation regulates HGF-induced epithelial branching morphogenesis Miao, Hui Nickel, Christian H. Cantley, Lloyd G. Bruggeman, Leslie A. Bennardo, Laura N. Wang, Bingcheng J Cell Biol Article Eph kinases and their ephrin ligands are widely expressed in epithelial cells in vitro and in vivo. Our results show that activation of endogenous EphA kinases in Madin-Darby canine kidney (MDCK) cells negatively regulates hepatocyte growth factor/scatter factor (HGF)–induced branching morphogenesis in collagen gel. Cotreatment with HGF and ephrin-A1 reduced sprouting of cell protrusions, an early step in branching morphogenesis. Moreover, addition of ephrin-A1 after HGF stimulation resulted in collapse and retraction of preexisting cell protrusions. In a newly developed assay that simulates the localized interactions between Ephs and ephrins in vivo, immobilized ephrin-A1 suppressed HGF-induced MDCK cell scattering. Ephrin-A1 inhibited basal ERK1/2 mitogen-activated protein kinase activity; however, the ephrin-A1 effect on cell protrusion was independent of the mitogen-activated protein kinase pathway. Ephrin-A1 suppressed HGF-induced activation of Rac1 and p21-activated kinase, whereas RhoA activation was retained, leading to the preservation of stress fibers. Moreover, dominant-negative RhoA or inhibitor of Rho-associated kinase (Y27632) substantially negated the inhibitory effects of ephrin-A1. These data suggest that interfering with c-Met signaling to Rho GTPases represents a major mechanism by which EphA kinase activation inhibits HGF-induced MDCK branching morphogenesis. The Rockefeller University Press 2003-09-29 /pmc/articles/PMC2173949/ /pubmed/14517207 http://dx.doi.org/10.1083/jcb.200304018 Text en Copyright © 2003, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Article
Miao, Hui
Nickel, Christian H.
Cantley, Lloyd G.
Bruggeman, Leslie A.
Bennardo, Laura N.
Wang, Bingcheng
EphA kinase activation regulates HGF-induced epithelial branching morphogenesis
title EphA kinase activation regulates HGF-induced epithelial branching morphogenesis
title_full EphA kinase activation regulates HGF-induced epithelial branching morphogenesis
title_fullStr EphA kinase activation regulates HGF-induced epithelial branching morphogenesis
title_full_unstemmed EphA kinase activation regulates HGF-induced epithelial branching morphogenesis
title_short EphA kinase activation regulates HGF-induced epithelial branching morphogenesis
title_sort epha kinase activation regulates hgf-induced epithelial branching morphogenesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2173949/
https://www.ncbi.nlm.nih.gov/pubmed/14517207
http://dx.doi.org/10.1083/jcb.200304018
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