PMID:15831470

Citation	Leung-Hagesteijn, C, Hu, MC, Mahendra, AS, Hartwig, S, Klamut, HJ, Rosenblum, ND and Hannigan, GE (2005) Integrin-linked kinase mediates bone morphogenetic protein 7-dependent renal epithelial cell morphogenesis. Mol. Cell. Biol. 25:3648-57
Abstract	Bone morphogenetic protein 7 (BMP7) stimulates renal branching morphogenesis via p38 mitogen-activated protein kinase (p38(MAPK)) and activating transcription factor 2 (ATF-2) (M. C. Hu, D. Wasserman, S. Hartwig, and N. D. Rosenblum, J. Biol. Chem. 279:12051-12059, 2004). Here, we demonstrate a novel role for integrin-linked kinase (ILK) in mediating renal epithelial cell morphogenesis in embryonic kidney explants and identify p38(MAPK) as a target of ILK signaling in a cell culture model of renal epithelial morphogenesis. The spatial and temporal expression of ILK in embryonic mouse kidney cells suggested a role in branching morphogenesis. Adenovirus-mediated expression of ILK stimulated and expression of a dominant negative ILK mutant inhibited ureteric bud branching in embryonic mouse kidney explants. BMP7 increased ILK kinase activity in inner medullary collecting duct 3 (IMCD-3) cells, and adenovirus-mediated expression of ILK increased IMCD-3 cell morphogenesis in a three-dimensional culture model. In contrast, treatment with a small molecule ILK inhibitor or expression of a dominant negative-acting ILK (ILK(E359K)) inhibited epithelial cell morphogenesis. Further, expression of ILK(E359K) abrogated BMP7-dependent stimulation. To investigate the role of ILK in BMP7 signaling, we showed that ILK overexpression increased basal and BMP7-induced levels of phospho-p38(MAPK) and phospho-ATF-2. Consistent with its inhibitory effects on IMCD-3 cell morphogenesis, expression of ILK(E359K) blocked BMP7-dependent increases in phospho-p38(MAPK) and phospho-ATF-2. Inhibition of p38(MAPK) activity with the specific inhibitor, SB203580, failed to inhibit BMP7-dependent stimulation of ILK activity, suggesting that ILK functions upstream of p38(MAPK) during BMP7 signaling. We conclude that ILK functions in a BMP7/p38(MAPK)/ATF-2 signaling pathway and stimulates epithelial cell morphogenesis.
Links	PubMed PMC1084303 Online version:10.1128/MCB.25.9.3648-3657.2005
Keywords	Activating Transcription Factor 2; Animals; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins/pharmacology; Bone Morphogenetic Proteins/physiology; Cell Line; Cyclic AMP Response Element-Binding Protein/metabolism; Epithelium/drug effects; Epithelium/embryology; Epithelium/metabolism; Imidazoles/pharmacology; Kidney/cytology; Kidney/embryology; Mice; Morphogenesis/drug effects; Morphogenesis/genetics; Morphogenesis/physiology; Mutation/genetics; Protein-Serine-Threonine Kinases/genetics; Protein-Serine-Threonine Kinases/metabolism; Protein-Serine-Threonine Kinases/physiology; Pyridines/pharmacology; Signal Transduction; Transcription Factors/metabolism; Transforming Growth Factor beta/pharmacology; Transforming Growth Factor beta/physiology; p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases/metabolism
edit table

Annotations

Gene product	Qualifier	GO ID	GO term name	Evidence Code	with/from	Aspect	Notes	Status
edit table

References

See Help:References for how to manage references in GONUTS.