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PMID:27577745

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Citation

Nagarajan, A, Petersen, MC, Nasiri, AR, Butrico, G, Fung, A, Ruan, HB, Kursawe, R, Caprio, S, Thibodeau, J, Bourgeois-Daigneault, MC, Sun, L, Gao, G, Bhanot, S, Jurczak, MJ, Green, MR, Shulman, GI and Wajapeyee, N (2016) MARCH1 regulates insulin sensitivity by controlling cell surface insulin receptor levels. Nat Commun 7:12639

Abstract

Insulin resistance is a key driver of type 2 diabetes (T2D) and is characterized by defective insulin receptor (INSR) signalling. Although surface INSR downregulation is a well-established contributor to insulin resistance, the underlying molecular mechanisms remain obscure. Here we show that the E3 ubiquitin ligase MARCH1 impairs cellular insulin action by degrading cell surface INSR. Using a large-scale RNA interference screen, we identify MARCH1 as a negative regulator of INSR signalling. March1 loss-of-function enhances, and March1 overexpression impairs, hepatic insulin sensitivity in mice. MARCH1 ubiquitinates INSR to decrease cell surface INSR levels, but unlike other INSR ubiquitin ligases, MARCH1 acts in the basal state rather than after insulin stimulation. Thus, MARCH1 may help set the basal gain of insulin signalling. MARCH1 expression is increased in white adipose tissue of obese humans, suggesting that MARCH1 contributes to the pathophysiology of T2D and could be a new therapeutic target.

Links

PubMed Online version:10.1038/ncomms12639

Keywords


Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:FOXO1

GO:0045944: positive regulation of transcription from RNA polymerase II promoter

ECO:0000315:

P

Figure 6C and D show that shRNA-mediated knockdown of FOXO1 decrease expression of MARCH1. Figure 6G shows that, while insulin is absent, FOXO1 binds to the MARCH1 promoter, and while insulin is present, FOXO1 binding is inhibited.

complete
CACAO 12112

HUMAN:MARH1

GO:0000209: protein polyubiquitination

ECO:0000315:

P

Figure 8C shows that wild-type MARCH1 polyubiquitinates INSR beta, while MARCH1 that is E3-ligase activity-defective does not. Figure 8D demonstrates that, in cells, knockdown of MARCH1 results in a decrease in INSR beta ubiquitination.

complete
CACAO 12111

Notes

See also

References

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