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.
AuthorsYoung-Sil Yoon, Min-Woo Lee, Dongryeol Ryu, Jeong Ho Kim, Hui Ma, Woo-Young Seo, Yo-Na Kim, Su Sung Kim, Chul Ho Lee, Tony Hunter, Cheol Soo Choi, Marc R Montminy, Seung-Hoi Koo
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 107 Issue 41 Pg. 17704-9 (Oct 12 2010) ISSN: 1091-6490 [Electronic] United States
PMID20876121 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Crtc2 protein, mouse
  • Ppargc1a protein, mouse
  • Protein Subunits
  • Trans-Activators
  • Transcription Factors
  • Phosphoprotein Phosphatases
  • protein phosphatase 4
  • Animals
  • Blotting, Western
  • Chromatin Immunoprecipitation
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression Regulation (physiology)
  • Gluconeogenesis (physiology)
  • Immunoprecipitation
  • Liver (metabolism, physiology)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phosphoprotein Phosphatases (metabolism)
  • Phosphorylation
  • Protein Subunits (metabolism)
  • Rats
  • Rats, Sprague-Dawley
  • Trans-Activators (metabolism)
  • Transcription Factors

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