title: Hepatocyte growth factor (Hgf) stimulates low density lipoprotein receptor-related protein (Lrp) 5/6 phosphorylation and promotes canonical Wnt signaling.
abstract: While Wnt and Hgf signaling pathways are known to regulate epithelial cell responses during injury and repair, whether they exhibit functional cross-talk is not well defined. Canonical Wnt signaling is initiated by the phosphorylation of the Lrp5/6 co-receptors. In the current study we demonstrate that Hgf stimulates Met and Gsk3-dependent and Wnt-independent phosphorylation of Lrp5/6 at three separate activation motifs in subconfluent, de-differentiated renal epithelial cells. Hgf treatment stimulates the selective association of active Gsk3 with Lrp5/6. In contrast, Akt-phosphorylated inactive Gsk3 is excluded from this association. Hgf stimulates β-catenin stabilization and nuclear accumulation and protects against epithelial cell apoptosis in an Lrp5/6-dependent fashion. In vivo, the increase in Lrp5/6 phosphorylation and β-catenin stabilization in the first 6-24 h after renal ischemic injury was significantly reduced in mice lacking Met receptor in the renal proximal tubule. Our results thus identify Hgf as an important transactivator of canonical Wnt signaling that is mediated by Met-stimulated, Gsk3-dependent Lrp5/6 phosphorylation.
authors.affiliation: From the Section of Nephrology, Department of Internal Medicine and farrukh.koraishy@yale.edu.
authors.forename: Farrukh M
authors.initials: FM
authors.lastname: Koraishy
authors.affiliation: the Section of Pediatric Nephrology, Connecticut Children's Medical Center, Hartford, Connecticut 06106.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Silva
authors.affiliation: the Section of Pediatric Nephrology, Connecticut Children's Medical Center, Hartford, Connecticut 06106.
authors.forename: Sherene
authors.initials: S
authors.lastname: Mason
authors.affiliation: the Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510 and.
authors.forename: Dianqing
authors.initials: D
authors.lastname: Wu
authors.affiliation: From the Section of Nephrology, Department of Internal Medicine and.
authors.forename: Lloyd G
authors.initials: LG
authors.lastname: Cantley
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D055785:Gene Knockdown Techniques; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D007511:Ischemia / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000473:pathology; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051176:beta Catenin; D017228:Hepatocyte Growth Factor
keywords: Beta-catenin; Glycogen synthase kinase 3; Hepatocyte growth factor; Kidney; Wnt signaling