title: Deleting the TGF-β receptor in proximal tubules impairs HGF signaling.
abstract: Transforming growth factor-β (TGF-β) and hepatocyte growth factor (HGF) play key roles in regulating the response to renal injury but are thought to mediate divergent effects on cell behavior. However, how TGF-β signaling alters the response to HGF in epithelia, the key site of HGF signaling in the injured kidney, is not well studied. Contrary to our expectation, we showed that deletion of the TGF-β type II receptor in conditionally immortalized proximal tubule (PT) cells impaired HGF-dependent signaling. This reduced signaling was due to decreased transcription of c-Met, the HGF receptor, and the TGF-β-dependent c-Met transcription and increased response to HGF in PT cells were mediated by the Notch pathway. The interactions of TGF-β, HGF, and Notch pathways had biologically significant effects on branching morphogenesis, cell morphology, migration, and proliferation. In conclusion, epithelial TGF-β signaling promotes HGF signaling in a Notch-dependent pathway. These findings suggest that TGF-β modulates PT responses not only by direct effects, but also by affecting other growth factor signaling pathways.
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt Medical Center, Nashville, Tennessee;
authors.forename: Stellor
authors.initials: S
authors.lastname: Nlandu Khodo
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt Medical Center, Nashville, Tennessee;
authors.forename: Surekha
authors.initials: S
authors.lastname: Neelisetty
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt Medical Center, Nashville, Tennessee;
authors.forename: Luke
authors.initials: L
authors.lastname: Woodbury
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt Medical Center, Nashville, Tennessee;
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Green
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt Medical Center, Nashville, Tennessee; Department of Molecular Physiology and Biophysics, Vanderbilt Medical Center, Nashville, Tennessee; Department of Medicine, Veterans Affairs Hospital, Tennessee Valley Healthcare System, Nashville, Tennessee.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Harris
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt Medical Center, Nashville, Tennessee; Department of Cancer Biology, Vanderbilt Medical Center, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt Medical Center, Nashville, Tennessee; Department of Medicine, Veterans Affairs Hospital, Tennessee Valley Healthcare System, Nashville, Tennessee.
authors.forename: Roy
authors.initials: R
authors.lastname: Zent
authors.affiliation: Department of Research, Veterans Affairs Hospital, Tennessee Valley Healthcare System, Nashville, Tennessee; and Division of Nephrology, Department of Medicine, Vanderbilt Medical Center, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt Medical Center, Nashville, Tennessee; l.gewin@vanderbilt.edu.
authors.forename: Leslie
authors.initials: L
authors.lastname: Gewin
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D002478:Cells, Cultured; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D051880:Receptors, Notch / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C553307:HGF protein, mouse; D051880:Receptors, Notch; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D053829:Amyloid Precursor Protein Secretases
keywords: Notch signaling; growth factors; proximal tubule; transforming growth factor-β type II receptor