Protein kinase a is a negative regulator of renal branching morphogenesis and modulates inhibitory and stimulatory bone morphogenetic proteins

Protein kinase A (PKA) regulates morphogenetic responses to bone morphogene tic proteins (BMPs) during embryogenesis. However, the mechanisms by which PKA regulates BMP function are unknown. During kidney development, BMP-2 an d 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., Grinfe ld, B., Pei, Y., Attisano, L., Wrana, J. L., and Rosenblum, N. D. (1997) Am . J. Physiol. 273, F961-F975). We examined the interactions between PI(A an d these BMPs in embryonic kidney explants and in the mouse inner medullary collecting duct-3 model of collecting duct morphogenesis. H-89, an inhibito r of PKA, stimulated branching morphogenesis and enhanced the stimulatory e ffect of low doses of BMP-7 on tubule formation. Furthermore, H-89 rescued the inhibition of tubulogenesis by BMP-S (or high doses of BMP-7) by attenu ating BMP-a-induced collecting duct apoptosis. In contrast, 8-bromo-cAMP, a n activator of PKA, inhibited tubule formation and attenuated the stimulato ry effects of low doses of BMP-7. To determine mechanisms underlying the in terdependence of BMP signaling and PKA activity, we examined the effect of PKA on the known signaling events in the BMP-2-dependent Smad1 signaling pa thway and the effect of BMP-2 on PKA activity. PKA did not induce endogenou s Smad1 phosphorylation, Smad1-Smad4 complex formation, or Smad1 nuclear tr anslocation. In contrast, BMP-2 increased endogenous PKA activity and induc ed phosphorylation of the PKA effector, cAMP-response element-binding prote in, 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 morphoge nesis without activating the known signaling events in the BMP-2-dependent Smad1 signaling pathway.