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J Biol Chem, Vol. 273, Issue 40, 25628-25636, October 2, 1998
,,
,**, and**
From the BMP7 and activin are members of the transforming
growth factor Program in Developmental Biology, Department of Genetics, The Hospital
for Sick Children, Toronto, Ontario M5G 1X8, Canada, and the
** Department of Medical Genetics and Microbiology, University of
Toronto, Toronto, Ontario M5S 1A8, Canada
superfamily. Here we characterize endogenous activin
and BMP7 signaling pathways in P19 embryonic carcinoma cells. We show that BMP7 and activin bind to the same type II receptors, ActRII and
IIB, but recruit distinct type I receptors into heteromeric receptor
complexes. The major BMP7 type I receptor observed was ALK2, while
activin bound exclusively to ALK4 (ActRIB). BMP7 and activin elicited
distinct biological responses and activated different Smad pathways.
BMP7 stimulated phosphorylation of endogenous Smad1 and 5, formation of
complexes with Smad4 and induced the promoter for the homeobox gene,
Tlx2. In contrast, activin induced phosphorylation of
Smad2, association with Smad4, and induction of the activin response
element from the Xenopus Mix.2
gene. Biochemical analysis revealed that constitutively active ALK2
associated with and phosphorylated Smad1 on the COOH-terminal
SSXS motif, and also regulated Smad5 and Smad8
phosphorylation. Activated ALK2 also induced the Tlx2 promoter in the absence of BMP7. Furthermore, we show that ALK1 (TSRI),
an orphan receptor that is closely related to ALK2 also mediates Smad1
signaling. Thus, ALK1 and ALK2 induce Smad1-dependent pathways and ALK2 functions to mediate BMP7 but not activin
signaling.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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