Intracellular signaling of osteogenic protein-1 through Smad5 activation

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Abstract
Smad proteins play pivotal roles in the intracellular signaling of the multifunctional transforming growth factor‐β (TGF‐β) family members downstream of serine/threonine kinase type I and type II receptors. Smad2 and Smad3 are specific mediators of TGF‐β and activin, while Smad1 and Smad5 are involved in bone morphogenetic protein‐2 (BMP‐2) and BMP‐4 signaling. Here we report that osteogenic protein‐1 (OP‐1), also termed BMP‐7, binds predominantly to BMPR‐IB in the rat osteoprogenitor‐like cell line, ROB‐C26. Smad1, Smad5, and Smad8, but not Smad2 and Smad3, were found to stably interact with the kinase‐deficient BMPR‐IB after it was phosphorylated by the BMPR‐II kinase. In ROB‐C26 cells, which express Smad2, Smad3, Smad4, and Smad5, OP‐1 was found to stimulate the phosphorylation of Smad5. Whereas transfection of wild‐type Smad5 enhanced the OP‐1‐induced response, transfection of wild‐type Smad2 had no effect on OP‐1 signaling. A Smad5‐2SA mutant, in which the two most carboxy‐terminal serine residues were mutated to alanine residues, was found to act as a dominant negative inhibitor of OP‐1‐induced responses upon its transfection into various cell types, including ROB‐C26 cells, in contrast to ectopic expression of a Smad2‐2SA mutant which was without effect. Smad5, therefore, is a key component in the intracellular signaling of OP‐1. J. Cell. Physiol. 177:355–363, 1998.

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