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J Biol Chem. 2015 Oct 2;290(40):24255-66. doi: 10.1074/jbc.M115.658559. Epub 2015 Aug 14.

Prolyl isomerase Pin1 negatively regulates AMP-activated protein kinase (AMPK) by associating with the CBS domain in the γ subunit.

Author information

1
From the Department of Medical Science, Graduate School of Medicine.
2
the Department of Dental Science for Health Promotion, Graduate School of Biomedical Science, and.
3
the Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
4
the Department of Endocrinology and Diabetes, School of Medicine, Saitama Medical University, Moroyama, Saitama 350-0495, Japan.
5
the Division of Diabetes and Metabolism, Institute for Adult Disease, Asahi Life Foundation, 1-6-1 Marunouchi, Chiyoda-ku, Tokyo 103-0002, Japan.
6
the Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
7
the Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
8
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.
9
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.
10
the Department of Molecular Cell Biology, Graduate School of Agricultural Science, Tohoku University Sendai, Miyagi 981-8555, Japan.
11
From the Department of Medical Science, Graduate School of Medicine, tasano@hiroshima-u.ac.jp.

Abstract

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.

KEYWORDS:

AMP-activated kinase (AMPK); diabetes; energy metabolism; lipid metabolism; metabolic syndrome; muscle; prolyl isomerase

PMID:
26276391
PMCID:
PMC4591812
DOI:
10.1074/jbc.M115.658559
[Indexed for MEDLINE]
Free PMC Article

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