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Am J Physiol Heart Circ Physiol. 2016 May 1;310(9):H1184-93. doi: 10.1152/ajpheart.00782.2015. Epub 2016 Feb 26.

The neuropilin-like protein ESDN regulates insulin signaling and sensitivity.

Author information

1
Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale School of Medicine, New Haven, Connecticut; Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China;
2
Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale School of Medicine, New Haven, Connecticut; Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut;
3
Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale School of Medicine, New Haven, Connecticut; Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut; Department of Biochemistry and Molecular Biology, Hebei Medical University, Shijiazhuang, China; and.
4
Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut; Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.
5
Section of Cardiovascular Medicine and Cardiovascular Research Center, Yale School of Medicine, New Haven, Connecticut; Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut; Mehran.sadeghi@yale.edu.

Abstract

Insulin effects on cell metabolism, growth, and survival are mediated by its binding to, and activation of, insulin receptor. With increasing prevalence of insulin resistance and diabetes there is considerable interest in identifying novel regulators of insulin signal transduction. The transmembrane protein endothelial and smooth muscle cell-derived neuropilin-like protein (ESDN) is a novel regulator of vascular remodeling and angiogenesis. Here, we investigate a potential role of ESDN in insulin signaling, demonstrating that Esdn gene deletion promotes insulin-induced vascular smooth muscle cell proliferation and migration. This is associated with enhanced protein kinase B and mitogen-activated protein kinase activation as well as insulin receptor phosphorylation. Likewise, insulin signaling in the liver, muscle, and adipose tissue is enhanced in Esdn(-/-) mice, and these animals exhibit improved insulin sensitivity and glucose homeostasis in vivo. The effect of ESDN on insulin signaling is traced back to its interaction with insulin receptor, which alters the receptor interaction with regulatory adaptor protein-E3 ubiquitin ligase pairs, adaptor protein with pleckstrin homology and Src homology 2 domain-c-Cbl and growth factor receptor bound protein 10-neuronal precursor cell-expressed developmentally downregulated 4. In conclusion, our findings establish ESDN as an inhibitor of insulin receptor signal transduction through a novel regulatory mechanism. Loss of ESDN potentiates insulin's metabolic and mitotic effects and provides insights into a novel therapeutic avenue.

KEYWORDS:

adaptor protein with pleckstrin homology and Src homology 2 domain; endothelial and smooth muscle cell-derived neuropilin-like protein; glucose homeostasis; insulin signaling

PMID:
26921437
PMCID:
PMC4867389
DOI:
10.1152/ajpheart.00782.2015
[Indexed for MEDLINE]
Free PMC Article

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