Functions And Mechanism Of Phosphatase SCP4 In TGFβ/BMP Signaling Pathways

Members of the Transforming Growth Factor-β (TGFP) family possess diverse functions in cell proliferation, differentiation, apoptosis, organogenesis and embryonic development. The Bone Morphogenetic Proteins (BMPs), belonging to the TGFP superfamily, regulates a wide range of cellular responses in metazoans, including cell and tissue differentiation, morphogenetic processes, limb development, axis specification, generation of primordial germ cells, and patterning of the neural tube. The activity of the BMP-initiated signaling pathways is under tight control by processes including regulation of the ligands, the receptors, secreted antagonists (e.g. noggin) and the downstream intracellular effector Smad proteins. Smad proteins are central signal transducers in the canonical BMP/TGFβ signaling. The most critical step in canonical BMP signaling is the ligand-induced phosphorylation of Smadl/5/8 in the C-terminal SXS motif, which is mediated by the BMP type I receptors. The SXS phosphorylation triggers a cascade of intracellular events from Smad complex assembly in the cytoplasm to transcriptional responses in the nucleus.Since signal transduction pathways are regulated by dynamic interplay between protein kinases and phosphatases, the SXS motif must be dephosphorylated by phosphatases to ensure proper balance of Smad signaling. In this study, we focused on how Smadl/5/8 is dephosphorylated. We first reported that a novel nuclear phosphatase named SCP4, belonging to the FCP/SCP family, physically interacts with and selectively dephosphorylates Smadl/5/8. Further gain-of-function and loss-of-function experiments demonstrate that SCP4 plays a critical role in BMP-induced signaling and mesenchymal cellular functions. In conclusion, SCP4 specifically dephosphorylates Smadl/5/8 and turns off Smad-mediated transcriptional activation in the BMP signaling pathway.Further investigation on SCP4 leads to our finding that SCP4 also plays an important role in epithelial-mesenchymal transition (EMT), which is critical in normal development and disease states such as tissue fibrosis and metastasis. Snail, a key transcription repressor of E-cadherin, is a labile protein with a short half-life and is regulated through phosphorylation, ubiquitination, and degradation. In this study, we have found SCP4 is a novel phosphatase for Snail. SCP4 interacts and co-localizes with Snail in the nucleus. SCP4 functions as a Snail phosphatase to control its phosphorylation and stabilization, and our study provides novel insights for the regulation of Snail during EMT and cancer metastasis.In summary, SCP4 regulates cellular functions in both TGFβ and BMP signaling pathways. On one hand, SCP4 acts as a novel nuclear phosphatase targeting BMP-induced Smads at SXS motif, further attenuating BMP signaling pathway and inhibiting osteoblast differentiation. On the other hand, SCP4 functions as a novel Snail phosphatase and enhances TGFβ signaling pathway and promotes EMT process and metastasis.