title: Suppressor of MEK null (SMEK)/protein phosphatase 4 catalytic subunit (PP4C) is a key regulator of hepatic gluconeogenesis.
abstract: Fasting promotes hepatic gluconeogenesis to maintain glucose homeostasis. The cAMP-response element binding protein (CREB)-regulated transcriptional coactivator 2 (CRTC2) is responsible for transcriptional activation of gluconeogenic genes and is critical for conveying the opposing hormonal signals of glucagon and insulin in the liver. Here, we show that suppressor of MEK null 1 (SMEK1) and SMEK2 [protein phosphatase 4 (PP4) regulatory subunits 3a and 3b, respectively] are directly involved in the regulation of hepatic glucose metabolism in mice. Expression of hepatic SMEK1/2 is up-regulated during fasting or in mouse models of insulin-resistant conditions in a Peroxisome Proliferator-Activated Receptor-gamma Coactivator 1α (PGC-1α)-dependent manner. Overexpression of SMEK promotes elevations in plasma glucose with increased hepatic gluconeogenic gene expression, whereas depletion of the SMEK proteins reduces hyperglycemia and enhances CRTC2 phosphorylation; the effect is blunted by S171A CRTC2, which is refractory to salt-inducible kinase (SIK)-dependent inhibition. Taken together, we would propose that mammalian SMEK/PP4C proteins are involved in the regulation of hepatic glucose metabolism through dephosphorylation of CRTC2.
authors.affiliation: Department of Molecular Cell Biology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Gyeonggi-do 440-746, Korea.
authors.forename: Young-Sil
authors.initials: YS
authors.lastname: Yoon
authors.forename: Min-Woo
authors.initials: MW
authors.lastname: Lee
authors.forename: Dongryeol
authors.initials: D
authors.lastname: Ryu
authors.forename: Jeong Ho
authors.initials: JH
authors.lastname: Kim
authors.forename: Hui
authors.initials: H
authors.lastname: Ma
authors.forename: Woo-Young
authors.initials: WY
authors.lastname: Seo
authors.forename: Yo-Na
authors.initials: YN
authors.lastname: Kim
authors.forename: Su Sung
authors.initials: SS
authors.lastname: Kim
authors.forename: Chul Ho
authors.initials: CH
authors.lastname: Lee
authors.forename: Tony
authors.initials: T
authors.lastname: Hunter
authors.forename: Cheol Soo
authors.initials: CS
authors.lastname: Choi
authors.forename: Marc R
authors.initials: MR
authors.lastname: Montminy
authors.forename: Seung-Hoi
authors.initials: SH
authors.lastname: Koo
mesh_terms: D000818:Animals; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000502:physiology*; D005943:Gluconeogenesis / Q000502:physiology*; D047468:Immunoprecipitation; D008099:Liver / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors
chemical_list: C504923:Crtc2 protein, mouse; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D021122:Protein Subunits; D015534:Trans-Activators; D014157:Transcription Factors; D010749:Phosphoprotein Phosphatases; C080406:protein phosphatase 4