期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 277, 期 36, 页码 33361-33368出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M205053200
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资金
- NIAMS NIH HHS [R01 AR042306, AR-42306] Funding Source: Medline
- NIDDK NIH HHS [R01 DK55815] Funding Source: Medline
The mechanism by which bone morphogenetic protein-2 (BMP-2) induces ostcoblast differentiation is not precisely known. We investigated the involvement of the phosphatidylinositol (PI) 3-kinase/Akt signal transduction pathway in modulation of this process. BMP-2 stimulated PI 3-kinase activity in osteogenic cells. Inhibition of PI 3-kinase activity with the specific inhibitor Ly-294002 prevented BNW-2-induced alkaline phosphatase, an early marker of osteoblast differentiation. Expression of dominant-negative PI 3-kinase also abolished osteoblastic induction of alkaline phosphatase in response to BMP-2, confirming the involvement of this lipid kinase in this process. BMP-2 stimulated Akt serine/threonine kinase activity in a PI 3-kinase-dependent manner in osteoblast precursor cells. Inhibition of Akt activity by a dominant-negative mutant of Akt blocked BMP-2-induced osteoblastic alkaline phosphatase activity. BMP-2 stimulates its own expression during osteoblast differentiation. Expression of dominantnegative PI 3-kinase or dominant-negative Akt inhibited BMP-2-induced BMP-2 transcription. Because all the known biological activities of BMP-2 are mediated by transcription via BMP-specific Smad proteins, we investigated the involvement of PI 3-kinase in Smad-dependent BMP-2 transcription. Smad5 stimulated BMP-2 transcription independent of addition of the ligand. Dominant-negative PI 3-kinase or dominant-negative Akt inhibited Smad5-dependent transcription of BMP-2. Furthermore dominant-negative Akt inhibited translocation of BMP-specific Smads into nucleus. Together these data provide the first evidence that activation of BMP receptor serine/threonine kinase stimulates the PI 3 kinase/Akt pathway and define a role for this signal transduction pathway in BMP-specific Smad function during osteoblast differentiation.
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