Specific Activation of Smad1 Signaling Pathways by the BMP7 Type I Receptor, ALK2

doi:10.1074/jbc.273.40.25628

Specific Activation of Smad1 Signaling Pathways by the BMP7 Type I Receptor, ALK2*

From the ^‡Program in Developmental Biology, Division of Gastroenterology, the ^‖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

Abstract

BMP7 and activin are members of the transforming growth factor β 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.2gene. 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 Tlx2promoter 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.

Footnotes

↵* This work was supported in part by grants from the Medical Research Council of Canada and the National Cancer Institute of Canada with funds from the Terry Fox Run (to J. L. W.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵§ Recipient of a Medical Research Council postdoctoral fellowship.
↵¶ Supported by Medical Research Council Centennial and Canadian Association of Gastroenterology fellowships.
↵‡ Medical Research Council Scholar. To whom correspondence should be addressed: Program in Developmental Biology, The Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada. Tel.: 416-813-5173; Fax: 416-813-6531; E-mail:jwrana{at}sickkids.on.ca.
↵2 J. L. Wrana, unpublished data.
Abbreviations:

TGFβ

transforming growth factor β

PAGE

polyacrylamide gel electrophoresis

ARE

activin response element.
- Received March 31, 1998.
- Revision received July 19, 1998.
The American Society for Biochemistry and Molecular Biology, Inc.