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.
Highlights
We have found that PPM1A acts as a phosphatase for TGF--activated Smad2 and Smad3 [16]
PPM1A Dephosphorylates Smad1—In a search to study Smad2/3 dephosphorylation in the phospho-SXS motif, we recently identified PPM1A as the phosphatase for Smad2 and Smad3 that is responsible for termination of TGF- signals (Lin et al, [16])
Bone morphogenetic proteins (BMPs)-induced Smad1 phosphorylation was analyzed in HeLa cells that were transfected with HA-Smad1 and His-PPM1A
Summary
Cells were transfected with reporter plasmids (e.g. GCCG-lux, Id1-luc, Xvent-luc, or FRluc) and expression plasmids for PPM1A and treated for 12 h with or without 25 ng/ml BMP2. BMP-induced Smad1 phosphorylation was analyzed in HeLa cells that were transfected with HA-Smad1 and His-PPM1A. In the absence of PPM1A, the level of P-Smad1 increased upon 1 h of BMP2 stimulation (Fig. 1A, lane 2).
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