Hepatocyte growth factor-mediated renal epithelial branching morphogenesis is regulated by glypican-4 expression.
The glypican (Gpc) family of cell surface heparan sulfate proteoglycans are expressed in a tissue-specific and developmentally regulated fashion. To determine if individual Gpcs can modulate heparin-binding growth factor signaling, we examined hepatocyte growth factor (HGF)-stimulated mitogenic, motogenic, and morphogenic responses of renal tubular cells expressing different Gpcs. Adult inner medullary collecting duct (IMCD) cells were found to express primarily Gpc4 and to proliferate, migrate, and form tubules with HGF, correlating with sustained extracellular signal-regulated kinase (ERK) activation. Embryonic IMCD cells expressing predominantly Gpc3 proliferated and migrated in response to HGF but activated ERK only transiently and failed to form tubules. Overexpressing Gpc-4 but not Gpc-3 or Gpc-1 led to sustained HGF-stimulated ERK activation and rescued the tubulogenic response in these cells. These results demonstrate that both signaling and phenotypic responses to HGF can be regulated by specific Gpc expression patterns.
Karihaloo
Anil
A
Division of Nephrology, Program in Development Biology, The Hospital for Sick Children, University of Toronto, Ontario, Canada. anil.karihaloo@yale.edu
Kale
Sujata
S
Rosenblum
Norman D
ND
Cantley
Lloyd G
LG
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D004815:Epidermal Growth Factor / Q000378:metabolism; D053673:Glypicans; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D007668:Kidney / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism
D053673:Glypicans; C115814:Gpc4 protein, mouse; D019812:Heparan Sulfate Proteoglycans; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met