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.
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.
H
H
Aoki
M
M
Fujii
T
T
Imamura
K
K
Yagi
K
K
Takehara
M
M
Kato
K
K
Miyazono
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