Protein phosphatase magnesium-dependent 1A-mediated inhibition of BMP signaling is independent of Smad dephosphorylation.
Phosphorylation of Smad1/5/8 at carboxyl-terminal serine residues by type I receptors activates downstream bone morphogenetic protein (BMP) signaling. Protein phosphatase magnesium-dependent 1A (PPM1A) has been shown to suppress BMP activity by dephosphorylating phospho-Smads. We report here that PPM1A suppresses BMP signaling via a novel mechanism. PPM1A inhibited a constitutively activated Smad1 mutant lacking BMP receptor phosphorylation sites. PPM1A reduced the protein levels not only of Smad1 but also of Smad5 and Smad8. A proteasome inhibitor blocked the inhibitory effects of PPM1A on Smad1, but the Smurf-binding motif in the Smad1 linker region was not involved in this inhibition. The phosphatase activity of PPM1A is essential for inhibition. Taken together, these findings suggest that through the dephosphorylation of unidentified substrate(s), PPM1A inhibits BMP signaling by decreasing Smad protein levels via the proteasome pathway. Moreover, knockdown of endogenous PPM1A stimulated osteoblastic differentiation, suggesting that PPM1A may physiologically suppress BMP signaling via Smads.
Kokabu
Shoichiro
S
Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.
Nojima
Junya
J
Kanomata
Kazuhiro
K
Ohte
Satoshi
S
Yoda
Tetsuya
T
Fukuda
Toru
T
Katagiri
Takenobu
T
D000818:Animals; D015153:Blotting, Western; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002478:Cells, Cultured; D055785:Gene Knockdown Techniques; D007150:Immunohistochemistry; D051379:Mice; D032446:Myoblasts / Q000187:drug effects*; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation; D000071636:Protein Phosphatase 2C; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051898:Smad1 Protein / Q000378:metabolism*
D019485:Bone Morphogenetic Proteins; D051898:Smad1 Protein; C522359:Mdp1 protein, mouse; D010749:Phosphoprotein Phosphatases; C000607466:Ppm1a protein, mouse; D000071636:Protein Phosphatase 2C