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Molecular and Cellular Biology, May 2005, p. 3648-3657, Vol. 25, No. 9
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.9.3648-3657.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Integrin-Linked Kinase Mediates Bone Morphogenetic Protein 7-Dependent Renal Epithelial Cell Morphogenesis

Chungyee Leung-Hagesteijn,1 Ming Chang Hu,2 Ahalya S. Mahendra,1,3,4 Sunny Hartwig,2,5 Henry J. Klamut,6,{dagger} Norman D. Rosenblum,2,3,5,7,8 and Gregory E. Hannigan1,3,4*

Cancer Research Program,1 Program in Developmental Biology, Research Institute,2 Division of Nephrology,5 Department of Pediatric Laboratory Medicine, Hospital for Sick Children,3 Ontario Cancer Institute, University Health Network,6 Departments of Laboratory Medicine and Pathobiology,4 Physiology,7 Paediatrics, University of Toronto, Toronto, Ontario, Canada8

Received 26 October 2004/ Returned for modification 22 November 2004/ Accepted 1 February 2005

Bone morphogenetic protein 7 (BMP7) stimulates renal branching morphogenesis via p38 mitogen-activated protein kinase (p38MAPK) 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 p38MAPK 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 (ILKE359K) inhibited epithelial cell morphogenesis. Further, expression of ILKE359K 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-p38MAPK and phospho-ATF-2. Consistent with its inhibitory effects on IMCD-3 cell morphogenesis, expression of ILKE359K blocked BMP7-dependent increases in phospho-p38MAPK and phospho-ATF-2. Inhibition of p38MAPK activity with the specific inhibitor, SB203580, failed to inhibit BMP7-dependent stimulation of ILK activity, suggesting that ILK functions upstream of p38MAPK during BMP7 signaling. We conclude that ILK functions in a BMP7/p38MAPK/ATF-2 signaling pathway and stimulates epithelial cell morphogenesis.

* Corresponding author. Mailing address: Cancer Research Program, Research Institute, Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada. Phone: (416) 813-8149. Fax: (416) 813-8883. E-mail: hannigan{at}sickkids.ca.

{dagger} Present address: Musculoskeletal Disease Center, Jerry L. Pettis Memorial VA Medical Center Department of Medicine, Loma Linda University, Loma Linda, Calif.

Molecular and Cellular Biology, May 2005, p. 3648-3657, Vol. 25, No. 9
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.9.3648-3657.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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