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translocate into the nucleus and regulate the transcription of various target genes.
Our recent finding, together with the finding that the MH2 domain of Smad 4
forms a trimer in solution, suggested that the hetero-oligomers may be
heterotrimers, composed of two and one molecules, or one and two molecules of
R-Smads and Smad 4, respectively.36 Although phosphorylated R-Smads can form
oligomers and translocate into the nucleus even in the absence of co-Smad, coSmad stabilizes the structures of the Smad oligomers and is thus required for
efficient transcriptional activity of the Smad complexes.
R-Smads activated by BMP receptors appear to be essential and probably
sufficient for the differentiation of osteoprogenitor cells into osteoblasts induced
by BMPs.24,34BMPs bind to three different type I receptors, i.e., ALK-3/BMPRIA, ALK-6/BMPR-IB, and ALK-2/ActR-I, which in turn activate Smads 1, 5, and
8. Smads 1 and 5 have been shown to induce the differentiation of C2C12 cells
even in the absence of stimulation by ligands or BMP receptors.
37
R-Smads are
observed throughout the cell in the absence of ligand stimulation and they cannot
efficiently induce differentiation of C2, C12 cells; however, R-Smads translocate
into the nucleus upon receptor activation, and induce cellular differentiation.
Nuclear translocation is thus one of the most critical events in the function of RSmads.