title: PPP3CC feedback regulates IP3-Ca2+ pathway through preventing ITPKC degradation.
abstract: ITPKC, a susceptibility gene of Kawasaki disease, encodes a kinase that negatively regulates intracellular Ca2+ level and inhibits calcineurin-dependent activation of NFAT by phosphorylating IP3. In this study, we identified a novel ITPKC-interacting protein, namely PPP3CC, using yeast two-hybrid. This interaction was further confirmed by GST pull-down and co-immunoprecipitation assays, and fluorescent microscopy showed co-localization of both proteins in the cell cytoplasm. Our functional studies demonstrated that PPP3CC positively influences the protein level of ITPKC, likely by inhibiting phosphorylation of ITPKC and consequently preventing ITPKC from ubiquitin-mediated protein degradation which requires phosphorylation. Importantly, the protein level of PPP3CC negatively correlates with the cellular level of IP3, suggesting a regulatory role of PPP3CC in the IP3-Ca2+ signaling pathway.
authors.affiliation: State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200433, PR China.
authors.forename: Pu
authors.initials: P
authors.lastname: Li
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Lin
authors.forename: Jingxuan
authors.initials: J
authors.lastname: Shan
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Wang
authors.forename: Tong
authors.initials: T
authors.lastname: Zhou
authors.forename: Zhenggang
authors.initials: Z
authors.lastname: Zhu
authors.forename: Keke
authors.initials: K
authors.lastname: Huo
mesh_terms: D001483:Base Sequence; D019703:Calcineurin / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D017931:DNA Primers; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D059748:Proteolysis; D020798:Two-Hybrid System Techniques
chemical_list: D017931:DNA Primers; D015544:Inositol 1,4,5-Trisphosphate; D011493:Protein Kinase C; D019703:Calcineurin; C525675:PPP3CC protein, human; D002118:Calcium