{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPPP1R14C encodes the protein KEPI, a kinase‐enhanced inhibitor of protein phosphatase 1 (PP1). Under basal conditions, KEPI is expressed in multiple tissues including brain, heart, and skeletal muscle, and its activity is potentiated following phosphorylation by protein kinase C. This modification dramatically increases KEPI's inhibitory potency toward PP1, thereby influencing the duration and magnitude of serine/threonine phosphorylation events that are important in various cellular signaling pathways, including those modulated by opioids. (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond these biochemical insights, genome-wide association studies have highlighted the potential clinical relevance of the PPP1R14C locus. In particular, fine-mapping of candidate regions in Kawasaki disease identified neighboring markers that were more significantly associated with the condition than the originally implicated variants, suggesting a putative role for PPP1R14C in inflammatory and cardiovascular pathologies. (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurther supporting its functional importance, a monoclonal antibody raised against KEPI has been used to characterize its expression in human brain and other species, laying the groundwork for future studies into its tumor suppressor potential. Complementary studies in zebrafish have revealed that KEPI functions as a negative regulator of uORF-mediated translation during endoplasmic reticulum stress by modulating eIF2α phosphorylation—an effect that appears context-dependent and underscores the complexity of its role in stress responses. In contrast, genetic association analysis in patients receiving aromatase inhibitors did not confirm a link between a common PPP1R14C variant and musculoskeletal adverse events. Together, these findings indicate that PPP1R14C/KEPI serves as a critical modulator of PP1 activity whose regulatory functions span from control of phosphorylation events and translation during stress to potential roles in inflammatory and neoplastic processes. (see."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Qing-Rong Liu, Ping-Wu Zhang, Qiaoxi Zhen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "KEPI, a PKC-dependent protein phosphatase 1 inhibitor regulated by morphine."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M107558200"}], "href": "https://doi.org/10.1074/jbc.M107558200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11812771"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11812771"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "David Burgner, Sonia Davila, Willemijn B Breunis, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A genome-wide association study identifies novel and functionally related susceptibility Loci for Kawasaki disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Genet (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pgen.1000319"}], "href": "https://doi.org/10.1371/journal.pgen.1000319"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19132087"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19132087"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Katjana Daskalow, Prisca Boisguerin, Burkhard Jandrig, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Generation of an antibody against the protein phosphatase 1 inhibitor KEPI and characterization of the epitope."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Anticancer Res (2010)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20592344"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20592344"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Hung-Chieh Lee, Chi-Cheng Hsieh, Huai-Jen Tsai "}, {"type": "b", "children": [{"type": "t", "text": "KEPI plays a negative role in the repression that accompanies translational inhibition guided by the uORF element of human CHOP transcript during stress response."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gene (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.gene.2021.146160"}], "href": "https://doi.org/10.1016/j.gene.2021.146160"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35031423"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35031423"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Yuqing Liang, Christina L Gersch, Jennifer Lehman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Attempted replication of pharmacogenetic association of variants in PPP1R14C and CCDC148 with aromatase inhibitor-induced musculoskeletal symptoms."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pharmacogenet Genomics (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/FPC.0000000000000522"}], "href": "https://doi.org/10.1097/FPC.0000000000000522"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38359166"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38359166"}]}]}]}