Protein kinase A is a negative regulator of renal branching morphogenesis and modulates inhibitory and stimulatory bone morphogenetic proteins
Por:
Gupta I.R., Piscione T.D., Grisaru S., Phant T., Macias-Silva M., Zhou X., Whiteside C., Wrana J.L., Rosenblum N.D.
Publicada:
1 ene 1999
Resumen:
Protein kinase A (PKA) regulates morphogenetic responses to bone morphogenetic proteins (BMPs) during embryogenesis. However, the mechanisms by which PKA regulates BMP function are unknown. During kidney development, BMP-2 and high doses of BMP-7 inhibit branching morphogenesis, whereas low doses of BMP-7 are stimulatory (Piscione, T. D., Yager, T. D., Gupta, I. R., Grinfeld, B., Pei, Y., Attisano, L., Wrana, J. L., and Rosenblum, N. D. (1997) Am. J. Physiol. 273, F961-F975). We examined the interactions between PKA and these BMPs in embryonic kidney explants and in the mouse inner medullary collecting duct-3 model of collecting duct morphogenesis. H-89, an inhibitor of PKA, stimulated branching morphogenesis and enhanced the stimulatory effect of low doses of BMP-7 on tubule formation. Furthermore, H- 89 rescued the inhibition of tubulogenesis by BMP-2 (or high doses of BMP-7) by attenuating BMP-2-induced collecting duct apoptosis. In contrast, 8-bromo- cAMP, an activator of PKA, inhibited tubule formation and attenuated the stimulatory effects of low doses of BMP-7. To determine mechanisms underlying the interdependence of BMP signaling and PKA activity, we examined the effect of PKA on the known signaling events in the BMP-2-dependent Smad1 signaling pathway and the effect of BMP-2 on PKA activity. PKA did not induce endogenous Smad1 phosphorylation, Smad1-Smad4 complex formation, or Smad1 nuclear translocation. In contrast, BMP-2 increased endogenous PKA activity and induced phosphorylation of the PKA effector, cAMP-response element- binding protein, in a PKA-dependent manner. We conclude that BMP-2 induces activation of PKA and that PKA regulates the effects of BMPs on collecting duct morphogenesis without activating the known signaling events in the BMP- 2-dependent Smad1 signaling pathway.
Filiaciones:
Gupta I.R.:
Division of Nephrology, Hospital for Sick Children, University of Toronto, Toronto, Ont., Canada
Program in Developmental Biology, Hospital for Sick Children, University of Toronto, Toronto, Ont. M5G 1X8, Canada
Piscione T.D.:
Division of Nephrology, Hospital for Sick Children, University of Toronto, Toronto, Ont., Canada
Program in Developmental Biology, Hospital for Sick Children, University of Toronto, Toronto, Ont. M5G 1X8, Canada
Grisaru S.:
Division of Nephrology, Hospital for Sick Children, University of Toronto, Toronto, Ont., Canada
Program in Developmental Biology, Hospital for Sick Children, University of Toronto, Toronto, Ont. M5G 1X8, Canada
Phant T.:
Division of Nephrology, Hospital for Sick Children, University of Toronto, Toronto, Ont., Canada
Program in Developmental Biology, Hospital for Sick Children, University of Toronto, Toronto, Ont. M5G 1X8, Canada
Macias-Silva M.:
Program in Developmental Biology, Hospital for Sick Children, University of Toronto, Toronto, Ont. M5G 1X8, Canada
Zhou X.:
Division of Nephrology, Toronto Hospital, University of Toronto, Toronto, Ont. M5G 1X8, Canada
Whiteside C.:
Division of Nephrology, Toronto Hospital, University of Toronto, Toronto, Ont. M5G 1X8, Canada
Wrana J.L.:
Program in Developmental Biology, Hospital for Sick Children, University of Toronto, Toronto, Ont. M5G 1X8, Canada
Rosenblum N.D.:
Division of Nephrology, Hospital for Sick Children, University of Toronto, Toronto, Ont., Canada
Program in Developmental Biology, Hospital for Sick Children, University of Toronto, Toronto, Ont. M5G 1X8, Canada
Division of Nephrology, Hospital for Sick Children, 555 University Ave., Toronto, Ont. M5G 1X8, Canada
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