Autoregulation of insulin receptor signaling through MFGE8 and the αvβ5 integrin.

Autor:	Datta R; Cardiovascular Research Institute, University of California, San Francisco, CA 94158., Lizama CO; Cardiovascular Research Institute, University of California, San Francisco, CA 94158., Soltani AK; Cardiovascular Research Institute, University of California, San Francisco, CA 94158.; Lung Biology Center, University of California, San Francisco, CA 94158., Mckleroy W; Cardiovascular Research Institute, University of California, San Francisco, CA 94158.; Lung Biology Center, University of California, San Francisco, CA 94158.; Divisions of Pulmonary and Critical Care and Endocrinology, Department of Medicine, University of California, San Francisco, CA 94143., Podolsky MJ; Cardiovascular Research Institute, University of California, San Francisco, CA 94158.; Divisions of Pulmonary and Critical Care and Endocrinology, Department of Medicine, University of California, San Francisco, CA 94143., Yang CD; Cardiovascular Research Institute, University of California, San Francisco, CA 94158., Huynh TL; Department of Radiology and Biomedical imaging, University of California, San Francisco, CA 94107., Cautivo KM; Department of Laboratory Medicine, University of California, San Francisco, CA 94143., Wang B; Cardiovascular Research Institute, University of California, San Francisco, CA 94158.; Department of Physiology, University of California, San Francisco, CA 94158., Koliwad SK; Divisions of Pulmonary and Critical Care and Endocrinology, Department of Medicine, University of California, San Francisco, CA 94143.; Diabetes Center, University of California, San Francisco, CA 94143., Abumrad NA; Diabetes Research Center, Department of Medicine and Cell Biology, Washington University in St. Louis, St. Louis, MO 63110., Atabai K; Cardiovascular Research Institute, University of California, San Francisco, CA 94158; kamran.atabai@ucsf.edu.; Lung Biology Center, University of California, San Francisco, CA 94158.; Divisions of Pulmonary and Critical Care and Endocrinology, Department of Medicine, University of California, San Francisco, CA 94143.; Department of Physiology, University of California, San Francisco, CA 94158.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 May 04; Vol. 118 (18).
DOI:	10.1073/pnas.2102171118
Abstrakt:	The role of integrins, in particular αv integrins, in regulating insulin resistance is incompletely understood. We have previously shown that the αvβ5 integrin ligand milk fat globule epidermal growth factor like 8 (MFGE8) regulates cellular uptake of fatty acids. In this work, we evaluated the impact of MFGE8 on glucose homeostasis. We show that acute blockade of the MFGE8/β5 pathway enhances while acute augmentation dampens insulin-stimulated glucose uptake. Moreover, we find that insulin itself induces cell-surface enrichment of MFGE8 in skeletal muscle, which then promotes interaction between the αvβ5 integrin and the insulin receptor leading to dampening of skeletal-muscle insulin receptor signaling. Blockade of the MFGE8/β5 pathway also enhances hepatic insulin sensitivity. Our work identifies an autoregulatory mechanism by which insulin-stimulated signaling through its cognate receptor is terminated through up-regulation of MFGE8 and its consequent interaction with the αvβ5 integrin, thereby establishing a pathway that can potentially be targeted to improve insulin sensitivity. Competing Interests: The authors declare no competing interest.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu