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Published 29 September 2003. doi:10.1083/jcb.200304018
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© The Rockefeller University Press, 0021-9525/2003/9/1281 $5.00
The Journal of Cell Biology, Volume 162, Number 7, 1281-1292

Article

 EphA kinase activation regulates HGF-induced epithelial branching morphogenesis

Hui Miao1, Christian H. Nickel2, Lloyd G. Cantley2, Leslie A. Bruggeman1, Laura N. Bennardo1 and Bingcheng Wang1

1 Rammelkamp Center for Research, MetroHealth Campus, and Department of Pharmacology and Ireland Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44109
2 School of Medicine, Yale University, New Haven, CT 06520

Address correspondence to Bingcheng Wang, Rammelkamp Center for Research, R421 MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109. Tel.: (216) 778-4256. Fax: (216) 778-4321. email: bxw14{at}cwru.edu

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.

Key Words: EphA2; ephrin-A1; Rho GTPases; kidney; MAPK

Abbreviations used in this paper: HGF, hepatocyte growth factor/scatter factor; PAK, p21-activated kinase; ROCK, Rho-associated kinase; RTK, receptor tyrosine kinases; SOIL, scattering onto immobilized ligands; UB, ureteric bud.


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