Synergistic effects of different bone morphogenetic protein type I receptors on alkaline phosphatase induction.
Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta superfamily, which regulate the differentiation of osteoprogenitor cells. Here we show that among members of the BMP family, BMP-4 and growth/differentiation factor 5 (GDF-5) induce osteoblast differentiation through the activation of three receptor-regulated Smads (i.e. Smad1, Smad5 and Smad8). By contrast, BMP-6 and BMP-7 induce alkaline phosphatase activity through Smad1 and Smad5, but not through Smad8. Consistent with these findings, BMP-4 induced phosphorylation and nuclear translocation of Smad1, Smad5 and Smad8, but BMP-6 activated only Smad1 and Smad5. BMP-4 and GDF-5 are known to bind to activin receptor-like kinase 3 (ALK-3) and/or ALK-6 (also termed BMP type IA and type IB receptors, respectively), whereas BMP-6 and BMP-7 preferentially bind to ALK-2. Compared with the effects induced by only one of the type I receptors, the combination of constitutively active forms of ALK-2 and ALK-3 (or ALK-6) more strongly induced alkaline phosphatase activity in C2C12 cells. Moreover, addition of BMP-4 and BMP-6 to C2C12 cells resulted in higher alkaline phosphatase activity than that of only one of these BMPs. The combination of ALK-2 and ALK-3 also induced higher transcriptional activity than either receptor alone. Thus, ALK-2 and ALK-3 (or ALK-6) might synergistically induce osteoblast differentiation of C2C12 cells, possibly through efficient activation of downstream signaling pathways.
Aoki
H
H
Dept of Biochemistry, The JFCR Cancer Institute, and Research for the Future Program, the Japan Society for the Promotion of Science, Toshima-ku, Tokyo 170-8455, Japan.
Fujii
M
M
Imamura
T
T
Yagi
K
K
Takehara
K
K
Kato
M
M
Miyazono
K
K
D029404:Activin Receptors; D000469:Alkaline Phosphatase / Q000096:biosynthesis*; D000818:Animals; D055395:Bone Morphogenetic Protein 1; D052004:Bone Morphogenetic Protein Receptors; D052005:Bone Morphogenetic Protein Receptors, Type I; D019485:Bone Morphogenetic Proteins / Q000737:chemistry / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D020033:Protein Isoforms / Q000737:chemistry; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000819:agonists / Q000378:metabolism*; D017978:Receptors, Growth Factor; D051785:Smad Proteins; D051898:Smad1 Protein; D051902:Smad5 Protein; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology; D014178:Translocation, Genetic
D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D010750:Phosphoproteins; D020033:Protein Isoforms; D011956:Receptors, Cell Surface; D017978:Receptors, Growth Factor; D051785:Smad Proteins; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D051902:Smad5 Protein; C497798:Smad5 protein, mouse; D015534:Trans-Activators; D017346:Protein Serine-Threonine Kinases; D029404:Activin Receptors; C498211:BMPR1A protein, human; C498214:BMPR1B protein, human; D052004:Bone Morphogenetic Protein Receptors; D052005:Bone Morphogenetic Protein Receptors, Type I; D000469:Alkaline Phosphatase; D008666:Metalloendopeptidases; C525707:Bmp1 protein, mouse; D055395:Bone Morphogenetic Protein 1