Protein serine/threonine phosphatase PPM1A dephosphorylates Smad1 in the bone morphogenetic protein signaling pathway

J Biol Chem. 2006 Dec 1;281(48):36526-32. doi: 10.1074/jbc.M605169200. Epub 2006 Aug 24.

Abstract

Bone morphogenetic proteins (BMPs) are secreted polypeptides belonging to the transforming growth factor-beta (TGF-beta) superfamily that activates a broad range of biological responses in the metazoan organism. The BMP-initiated signaling pathway is under tight control by processes including regulation of the ligands, the receptors, and the key downstream intracellular effector Smads. A critical point of control in BMP signaling is the phosphorylation of Smad1, Smad5, and Smad8 in their C-terminal SXS motif. Although such phosphorylation, which is mediated by the type I BMP receptor kinases in response to BMP stimulation, is well characterized, biochemical mechanisms underlying Smad dephosphorylation remain to be elucidated. In this study, we have found that PPM1A, a metal ion-dependent protein serine/threonine phosphatase, physically interacts with and dephosphorylates Smad1 both in vitro and in vivo. Functionally, overexpression of PPM1A abolishes BMP-induced transcriptional responses, whereas RNA interference-mediated knockdown of PPM1A enhances BMP signaling. Collectively, our study suggests that PPM1A plays an important role in controlling BMP signaling through catalyzing Smad dephosphorylation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Blotting, Western
  • Bone Morphogenetic Proteins / metabolism*
  • Catalysis
  • Cell Line
  • Humans
  • Immunoprecipitation
  • Phosphoprotein Phosphatases / chemistry*
  • Phosphoprotein Phosphatases / metabolism
  • Phosphorylation
  • Point Mutation
  • Protein Phosphatase 2C
  • Signal Transduction
  • Smad1 Protein / metabolism
  • Smad1 Protein / physiology*
  • Transfection
  • Transforming Growth Factor beta / metabolism

Substances

  • Bone Morphogenetic Proteins
  • Smad1 Protein
  • Transforming Growth Factor beta
  • PPM1A protein, human
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 2C