SPECIFIC ACTIVATION OF SMAD1 SIGNALING PATHWAYS BY THE BMP7 TYPE-I RECEPTOR, ALK2

BMP7 and activin are members of the transforming growth factor beta su perfamily. Here we characterize endogenous activin and BMP7 signaling pathways in P19 embryonic carcinoma cells. We show that BMP7 and activ in bind to the same type II receptors, ActRII and IIB, but recruit dis tinct type I receptors into heteromeric receptor complexes. The major BMP7 type I receptor observed was ALK2, while activin bound exclusivel y to ALK4 (ActRIB). BMP7 and activin elicited distinct biological resp onses and activated different Smad pathways. BMP7 stimulated phosphory lation of endogenous Smad1 and 5, formation of complexes with Smad4 an d induced the promoter for the homeobox gene, Tlx2. In contrast, activ in induced phosphorylation of Smad2, association with Smad4, and induc tion of the activin response element from the Xenopus Mix.2 gene. Bioc hemical analysis revealed that constitutively active ALK2 associated w ith and phosphorylated Smad1 on the COOH-terminal SSXS motif, and also regulated Smad5 and Smad8 phosphorylation. Activated ALK2 also induce d the Tlx2 promoter in the absence of BMP7. Furthermore, we show that ALK1 (TSRI), an orphan receptor that is closely related to ALK2 also m ediates Smad1 signaling. Thus, ALK1 and ALK2 induce Smad1-dependent pa thways and ALK2 functions to mediate BMP7 but not activin signaling.