Specific activation of Smad1 signaling pathways by the BMP7 type I receptor, ALK2.
BMP7 and activin are members of the transforming growth factor beta 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.
Macías-Silva
M
M
Program in Developmental Biology, Division of Gastroenterology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
Hoodless
P A
PA
Tang
S J
SJ
Buchwald
M
M
Wrana
J L
JL
D029404:Activin Receptors; D030201:Activin Receptors, Type I; D028341:Activins; D000818:Animals; D055396:Bone Morphogenetic Protein 2; D055419:Bone Morphogenetic Protein 7; D052005:Bone Morphogenetic Protein Receptors, Type I; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D007265:Inhibins / Q000502:physiology; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D017978:Receptors, Growth Factor / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins; D051898:Smad1 Protein; D051902:Smad5 Protein; D051904:Smad8 Protein; D015534:Trans-Activators / Q000378:metabolism*; D016212:Transforming Growth Factor beta; D015291:Transforming Growth Factors / Q000502:physiology; D014407:Tumor Cells, Cultured; D029867:Xenopus Proteins
C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D010750:Phosphoproteins; D017978:Receptors, Growth Factor; D051785:Smad Proteins; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D051902:Smad5 Protein; C497798:Smad5 protein, mouse; D051904:Smad8 Protein; C491622:Smad8 protein, Xenopus; C491621:Smad9 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D029867:Xenopus Proteins; C525822:bmp7.1 protein, Xenopus; D028341:Activins; D007265:Inhibins; D015291:Transforming Growth Factors; D017346:Protein Serine-Threonine Kinases; D029404:Activin Receptors; D030201:Activin Receptors, Type I; D052005:Bone Morphogenetic Protein Receptors, Type I