Suppressor of MEK null (SMEK)/protein phosphatase 4 catalytic subunit (PP4C) is a key regulator of hepatic gluconeogenesis.
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.
Yoon
Young-Sil
YS
Department of Molecular Cell Biology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Gyeonggi-do 440-746, Korea.
Lee
Min-Woo
MW
Ryu
Dongryeol
D
Kim
Jeong Ho
JH
Ma
Hui
H
Seo
Woo-Young
WY
Kim
Yo-Na
YN
Kim
Su Sung
SS
Lee
Chul Ho
CH
Hunter
Tony
T
Choi
Cheol Soo
CS
Montminy
Marc R
MR
Koo
Seung-Hoi
SH
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
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