title: Tissue-specific and nutrient regulation of the branched-chain α-keto acid dehydrogenase phosphatase, protein phosphatase 2Cm (PP2Cm).
abstract: Branched-chain amino acid (BCAA) homeostasis is maintained through highly regulated catabolic activities where the rate-limiting step is catalyzed by branched-chain α-keto dehydrogenase (BCKD). Our previous study has identified a mitochondria-targeted protein phosphatase, PP2Cm, as the BCKD phosphatase and thus serves as a key regulator for BCAA catabolism. In this report, we performed comprehensive molecular and biochemical studies of PP2Cm regulation using both in vivo and in vitro systems. We show that PP2Cm expression is highly enriched in brain, heart, liver, kidney, and diaphragm, but low in skeletal muscle. The PP2Cm expression is regulated at the transcriptional level in response to nutrient status. Furthermore, we have established that PP2Cm interacts with the BCKD E2 subunit and competes with the BCKD kinase in a substrate-dependent and mutually exclusive manner. These data suggest that BCAA homeostasis is at least in part contributed by nutrient-dependent PP2Cm expression and interaction with the BCKD complex. Finally, a number of human PP2Cm single nucleotide polymorphic changes as identified in the public data base can produce either inactive or constitutive active mutant phosphatases, suggesting that putative PP2Cm mutations may contribute to BCAA catabolic defects in human.
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Meiyi
authors.initials: M
authors.lastname: Zhou
authors.forename: Gang
authors.initials: G
authors.lastname: Lu
authors.forename: Chen
authors.initials: C
authors.lastname: Gao
authors.forename: Yibin
authors.initials: Y
authors.lastname: Wang
authors.forename: Haipeng
authors.initials: H
authors.lastname: Sun
mesh_terms: D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) / Q000378:metabolism; D000597:Amino Acids, Branched-Chain / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006706:Homeostasis; D006801:Humans; D015151:Immunoblotting; D007668:Kidney / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D008099:Liver / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D000071636:Protein Phosphatase 2C; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000597:Amino Acids, Branched-Chain; D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C