Regulation of GDF-8 signaling by the p38 MAPK.
Growth differentiation factor-8 (GDF-8), a member of the TGF-beta superfamily, 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 1 (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 inhibition of proliferation and upregulation of the cyclin kinase inhibitor p21. Together, these results highlight a functional link between 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.
Philip
Bevin
B
Protein Technologies Group, Wyeth Research, 87 Cambridge Park Drive, Cambridge MA 02140, USA.
Lu
Zhijian
Z
Gao
Yijie
Y
D051698:Activating Transcription Factor 2; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048669:MAP Kinase Kinase 6 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D032342:Muscle Cells / Q000378:metabolism*; D055435:Myostatin; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction; D051785:Smad Proteins; D051900:Smad3 Protein; D051901:Smad4 Protein; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000502:physiology*; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
D051698:Activating Transcription Factor 2; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D007093:Imidazoles; D048669:MAP Kinase Kinase 6; D020930:MAP Kinase Kinase Kinases; D055435:Myostatin; D011725:Pyridines; D051785:Smad Proteins; D051900:Smad3 Protein; D051901:Smad4 Protein; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C497105:ATF2 protein, human; C497106:Atf2 protein, mouse; C525911:MSTN protein, human; C525912:Mstn protein, mouse; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; C497791:Smad3 protein, mouse; C093642:SB 203580