p38MAPK Acts in the BMP7-dependent Stimulatory Pathway during Epithelial Cell Morphogenesis and Is Regulated by Smad1

Ming C Hu, David Wasserman, Sunny Hartwig, Norman D. Rosenblum

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48 Scopus citations

Abstract

Bone morphogenetic protein (BMP)-7 exerts dose-dependent stimulatory and inhibitory effects during renal branching morphogenesis. Previously, we identified an inhibitory role for activin-like kinase receptors and Smad1 in BMP-dependent inhibition (Piscione, T. D., Phan, T., and Rosenblum, N. D. (2001) Am. J. Physiol. 280, F19-F33). Here we demonstrate a novel role for p38 mitogen-activated kinase (p38MAPK) in BMP7-dependent stimulatory signaling. Stimulatory doses (0.25 nM) of BMP7 increased p38MAPK activity and stimulated phosphorylation of endogenous activating transcription factor 2 (ATF2) in a p38MAPK-dependent manner in murine inner medullary collecting duct (mIMCD-3) cells. In contrast, high doses (10 nM) of BMP7 inhibited p38MAPK activity and phosphorylation of endogenous ATF2. Treatment with BMP7 exerted no significant effect on the levels of the phosphorylated forms of endogenous SAPK/JNK or p44 and p42 (ERK1 and ERK2) protein kinases. To investigate the functional importance of p38MAPK signaling, we showed that SB203580, a p38MAPK inhibitor, blocked the stimulatory effect of BMP7 on mIMCD-3 cell morphogenesis but had no effect on BMP7-dependent inhibition in a three-dimensional culture model. To identify mechanisms by which BMP7-dependent inhibitory signaling suppresses p38 MAPK activity, we measured p38MAPK activity in ligand independent mIMCD-3 models of enhanced and suppressed Smad signaling. Basal activity of p38MAPK was decreased in mIMCD-3 cells and in embryonic kidney tissue expressing a constitutively active activin-like kinase receptor, but was increased in mIMCD-3 cells stably expressing a dominant negative form of Smad1. We conclude that BMP7 stimulates renal epithelial cell morphogenesis via p38MAPK and that p38MAPK activity is negatively regulated by Smad1.

Original languageEnglish (US)
Pages (from-to)12051-12059
Number of pages9
JournalJournal of Biological Chemistry
Volume279
Issue number13
DOIs
StatePublished - Mar 26 2004

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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