Regulation of GDF-8 signaling by the p38 MAPK

Growth differentiation factor-8 (GDF-8), a member of the TGF-beta super-family. is a negative regulator of skeletal muscle growth. which functions through activation of the Smad proteins. We found that GDF-8 can activate the p38 mitogen-activated protein kinase (MAPK) through the TGF-beta-activated kinase I (TAK1), and this appeared to be independent of Smad signaling. GDF-8-induced transcriptional activation was inhibited by expression of dominant negative MKK6 or treatment with the p38 inhibitor SB203580. while overexpression of wild-type forms of either MKK6 or p38 augmented GDF-8-induced transcriptional activity. In addition. ATF-2, a known transcription factor target of p38, was found to be phosphorylated on GDF-8 stimulation and was detected in a complex with Smad3/Smad4 upon GDF-8 treatment. Furthermore, we found that the p38 MAPK played an important role in GDF-8-induced 6 inhibition of proliferation and upregulation of the cyclin kinase inhibitor p21. Together. these results highlight a functional link the p38 MAPK and GDF-8-activated Smad pathways, and identify a critical role for the p38 MAPK in GDF-8's function as a negative regulator of muscle growth. (C) 2004 Elsevier Inc. All rights reserved.