Prolyl isomerase Pin1 negatively regulates AMP-activated protein kinase (AMPK) by associating with the CBS domain in the γ subunit.
AMP-activated protein kinase (AMPK) plays a critical role in metabolic regulation. In this study, first, it was revealed that Pin1 associates with any isoform of γ, but not with either the α or the β subunit, of AMPK. The association between Pin1 and the AMPK γ1 subunit is mediated by the WW domain of Pin1 and the Thr(211)-Pro-containing motif located in the CBS domain of the γ1 subunit. Importantly, overexpression of Pin1 suppressed AMPK phosphorylation in response to either 2-deoxyglucose or biguanide stimulation, whereas Pin1 knockdown by siRNAs or treatment with Pin1 inhibitors enhanced it. The experiments using recombinant Pin1, AMPK, LKB1, and PP2C proteins revealed that the protective effect of AMP against PP2C-induced AMPKα subunit dephosphorylation was markedly suppressed by the addition of Pin1. In good agreement with the in vitro data, the level of AMPK phosphorylation as well as the expressions of mitochondria-related genes, such as PGC-1α, which are known to be positively regulated by AMPK, were markedly higher with reduced triglyceride accumulation in the muscles of Pin1 KO mice as compared with controls. These findings suggest that Pin1 plays an important role in the pathogenic mechanisms underlying impaired glucose and lipid metabolism, functioning as a negative regulator of AMPK.
From the Department of Medical Science, Graduate School of Medicine.
Yusuke
Y
Nakatsu
the Department of Dental Science for Health Promotion, Graduate School of Biomedical Science, and.
Misaki
M
Iwashita
the Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Hideyuki
H
Sakoda
the Department of Endocrinology and Diabetes, School of Medicine, Saitama Medical University, Moroyama, Saitama 350-0495, Japan.
Hiraku
H
Ono
From the Department of Medical Science, Graduate School of Medicine.
Kengo
K
Nagata
From the Department of Medical Science, Graduate School of Medicine.
Yasuka
Y
Matsunaga
From the Department of Medical Science, Graduate School of Medicine.
Toshiaki
T
Fukushima
the Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Midori
M
Fujishiro
the Division of Diabetes and Metabolism, Institute for Adult Disease, Asahi Life Foundation, 1-6-1 Marunouchi, Chiyoda-ku, Tokyo 103-0002, Japan.
Akifumi
A
Kushiyama
From the Department of Medical Science, Graduate School of Medicine.
Hideaki
H
Kamata
the Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
Shin-Ichiro
S
Takahashi
the Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
Hideki
H
Katagiri
the Department of Disease Model, Research Institute of Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City 734-8553, Hiroshima, Japan.
Hiroaki
H
Honda
the Animal Resource Development Unit and Genetic Engineering Team, Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, 2-2-3 Minatojima Minami-machi, Chuou-ku, Kobe 650-0047, Japan, and.
Hiroshi
H
Kiyonari
the Department of Molecular Cell Biology, Graduate School of Agricultural Science, Tohoku University Sendai, Miyagi 981-8555, Japan.
Takafumi
T
Uchida
From the Department of Medical Science, Graduate School of Medicine, tasano@hiroshima-u.ac.jp.
Tomoichiro
T
Asano
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D020868:Gene Silencing; D005947:Glucose / Q000737:chemistry; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D050356:Lipid Metabolism; D024821:Metabolic Syndrome / Q000378:metabolism; D008687:Metformin / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009132:Muscles / Q000473:pathology; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism
D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D008687:Metformin; C526222:PRKAG1 protein, human; D055372:AMP-Activated Protein Kinases; D054648:Protein Phosphatase 2; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse; D005947:Glucose
AMP-activated kinase (AMPK); diabetes; energy metabolism; lipid metabolism; metabolic syndrome; muscle; prolyl isomerase