Integrin-linked kinase mediates bone morphogenetic protein 7-dependent renal epithelial cell morphogenesis

Chungyee Leung-Hagesteijn, Ming C Hu, Ahalya S. Mahendra, Sunny Hartwig, Henry J. Klamut, Norman D. Rosenblum, Gregory E. Hannigan

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)3648-3657
Number of pages10
JournalMolecular and Cellular Biology
Volume25
Issue number9
DOIs
StatePublished - May 2005

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Bone Morphogenetic Protein 7
Morphogenesis
Epithelial Cells
Kidney
p38 Mitogen-Activated Protein Kinases
Activating Transcription Factor 2
integrin-linked kinase
Adenoviridae

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Leung-Hagesteijn, C., Hu, M. C., Mahendra, A. S., Hartwig, S., Klamut, H. J., Rosenblum, N. D., & Hannigan, G. E. (2005). Integrin-linked kinase mediates bone morphogenetic protein 7-dependent renal epithelial cell morphogenesis. Molecular and Cellular Biology, 25(9), 3648-3657. https://doi.org/10.1128/MCB.25.9.3648-3657.2005

Integrin-linked kinase mediates bone morphogenetic protein 7-dependent renal epithelial cell morphogenesis. / Leung-Hagesteijn, Chungyee; Hu, Ming C; Mahendra, Ahalya S.; Hartwig, Sunny; Klamut, Henry J.; Rosenblum, Norman D.; Hannigan, Gregory E.

In: Molecular and Cellular Biology, Vol. 25, No. 9, 05.2005, p. 3648-3657.

Research output: Contribution to journalArticle

Leung-Hagesteijn, C, Hu, MC, Mahendra, AS, Hartwig, S, Klamut, HJ, Rosenblum, ND & Hannigan, GE 2005, 'Integrin-linked kinase mediates bone morphogenetic protein 7-dependent renal epithelial cell morphogenesis', Molecular and Cellular Biology, vol. 25, no. 9, pp. 3648-3657. https://doi.org/10.1128/MCB.25.9.3648-3657.2005
Leung-Hagesteijn, Chungyee ; Hu, Ming C ; Mahendra, Ahalya S. ; Hartwig, Sunny ; Klamut, Henry J. ; Rosenblum, Norman D. ; Hannigan, Gregory E. / Integrin-linked kinase mediates bone morphogenetic protein 7-dependent renal epithelial cell morphogenesis. In: Molecular and Cellular Biology. 2005 ; Vol. 25, No. 9. pp. 3648-3657.
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abstract = "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.",
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