The Beta Secretase BACE1 Regulates the Expression of Insulin Receptor in the Liver

Overview

Journal Nat Commun

Specialty Biology

Date 2018 Apr 4

PMID 29610518

Citations 32

Authors

Paul J Meakin

Anna Mezzapesa

Eva Benabou

Mary E Haas

Bernadette Bonardo

Michel Grino

Jean-Michel Brunel

Christele Desbois-Mouthon

Sudha B Biddinger

Roland Govers

Michael L J Ashford

Franck Peiretti

Affiliations

Soon will be listed here.

Abstract

Insulin receptor (IR) plays a key role in the control of glucose homeostasis; however, the regulation of its cellular expression remains poorly understood. Here we show that the amount of biologically active IR is regulated by the cleavage of its ectodomain, by the β-site amyloid precursor protein cleaving enzyme 1 (BACE1), in a glucose concentration-dependent manner. In vivo studies demonstrate that BACE1 regulates the amount of IR and insulin signaling in the liver. During diabetes, BACE1-dependent cleavage of IR is increased and the amount of IR in the liver is reduced, whereas infusion of a BACE1 inhibitor partially restores liver IR. We suggest the potential use of BACE1 inhibitors to enhance insulin signaling during diabetes. Additionally, we show that plasma levels of cleaved IR reflect IR isoform A expression levels in liver tumors, which prompts us to propose that the measurement of circulating cleaved IR may assist hepatic cancer detection and management.

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References

Yan R, Bienkowski M, Shuck M, Miao H, Tory M, Pauley A . Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature. 1999; 402(6761):533-7. DOI: 10.1038/990107. View

. Soluble insulin receptor ectodomain is elevated in the plasma of patients with diabetes. Diabetes. 2007; 56(8):2028-35. DOI: 10.2337/db07-0394. View

Morzyglod L, Cauzac M, Popineau L, Denechaud P, Fajas L, Ragazzon B . Growth factor receptor binding protein 14 inhibition triggers insulin-induced mouse hepatocyte proliferation and is associated with hepatocellular carcinoma. Hepatology. 2016; 65(4):1352-1368. DOI: 10.1002/hep.28972. View

Leibiger B, Leibiger I, Moede T, Kemper S, Kulkarni R, Kahn C . Selective insulin signaling through A and B insulin receptors regulates transcription of insulin and glucokinase genes in pancreatic beta cells. Mol Cell. 2001; 7(3):559-70. DOI: 10.1016/s1097-2765(01)00203-9. View

Frasca F, Pandini G, Scalia P, Sciacca L, MINEO R, Costantino A . Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells. Mol Cell Biol. 1999; 19(5):3278-88. PMC: 84122. DOI: 10.1128/MCB.19.5.3278. View

Olefsky J, Reaven G . Decreased insulin binding to lymphocytes from diabetic subjects. J Clin Invest. 1974; 54(6):1323-8. PMC: 301686. DOI: 10.1172/JCI107878. View

Taylor S, Kadowaki T, Kadowaki H, Accili D, Cama A, McKeon C . Mutations in insulin-receptor gene in insulin-resistant patients. Diabetes Care. 1990; 13(3):257-79. DOI: 10.2337/diacare.13.3.257. View

El Mesallamy H, Hamdy N, Mostafa D, Amin A . The serine protease granzyme B as an inflammatory marker, in relation to the insulin receptor cleavage in human obesity and type 2 diabetes mellitus. J Interferon Cytokine Res. 2013; 34(3):179-86. DOI: 10.1089/jir.2013.0059. View

Hattori C, Asai M, Onishi H, Sasagawa N, Hashimoto Y, Saido T . BACE1 interacts with lipid raft proteins. J Neurosci Res. 2006; 84(4):912-7. DOI: 10.1002/jnr.20981. View

10.

Johnson J, Chambers E, Jayasundera K . Application of a Bioinformatics-Based Approach to Identify Novel Putative in vivo BACE1 Substrates. Biomed Eng Comput Biol. 2014; 5:1-15. PMC: 4147752. DOI: 10.4137/BECB.S8383. View

11.

Hubbard S . The insulin receptor: both a prototypical and atypical receptor tyrosine kinase. Cold Spring Harb Perspect Biol. 2013; 5(3):a008946. PMC: 3578362. DOI: 10.1101/cshperspect.a008946. View

12.

Leconte I, Carpentier J, Clauser E . The functions of the human insulin receptor are affected in different ways by mutation of each of the four N-glycosylation sites in the beta subunit. J Biol Chem. 1994; 269(27):18062-71. View

13.

Kasuga K, Kaneko H, Nishizawa M, Onodera O, Ikeuchi T . Generation of intracellular domain of insulin receptor tyrosine kinase by gamma-secretase. Biochem Biophys Res Commun. 2007; 360(1):90-6. DOI: 10.1016/j.bbrc.2007.06.022. View

14.

Kadowaki H, Takahashi Y, Ando A, Momomura K, Kaburagi Y, Quin J . Four mutant alleles of the insulin receptor gene associated with genetic syndromes of extreme insulin resistance. Biochem Biophys Res Commun. 1997; 237(3):516-20. DOI: 10.1006/bbrc.1997.7181. View

15.

Creemers J, Ines Dominguez D, Plets E, Serneels L, Taylor N, Multhaup G . Processing of beta-secretase by furin and other members of the proprotein convertase family. J Biol Chem. 2000; 276(6):4211-7. DOI: 10.1074/jbc.M006947200. View

16.

Belfiore A, Malaguarnera R, Vella V, Lawrence M, Sciacca L, Frasca F . Insulin Receptor Isoforms in Physiology and Disease: An Updated View. Endocr Rev. 2017; 38(5):379-431. PMC: 5629070. DOI: 10.1210/er.2017-00073. View

17.

Nagarajan A, Petersen M, Nasiri A, Butrico G, Fung A, Ruan H . MARCH1 regulates insulin sensitivity by controlling cell surface insulin receptor levels. Nat Commun. 2016; 7:12639. PMC: 5013666. DOI: 10.1038/ncomms12639. View

18.

Meakin P, Harper A, Hamilton D, Gallagher J, McNeilly A, Burgess L . Reduction in BACE1 decreases body weight, protects against diet-induced obesity and enhances insulin sensitivity in mice. Biochem J. 2011; 441(1):285-96. PMC: 3242510. DOI: 10.1042/BJ20110512. View

19.

Song R, Peng W, Zhang Y, Lv F, Wu H, Guo J . Central role of E3 ubiquitin ligase MG53 in insulin resistance and metabolic disorders. Nature. 2013; 494(7437):375-9. DOI: 10.1038/nature11834. View

20.

Turner 3rd R, Koelsch G, Hong L, Castanheira P, Ermolieff J, Ghosh A . Subsite specificity of memapsin 2 (beta-secretase): implications for inhibitor design. Biochemistry. 2001; 40(34):10001-6. DOI: 10.1021/bi015546s. View