MFGE8 inhibits insulin signaling through PTP1B.

Autor:	Datta R; Cardiovascular Research Institute, University of California, San Francisco, CA 94158., Podolsky MJ; Cardiovascular Research Institute, University of California, San Francisco, CA 94158., Yang CD; Cardiovascular Research Institute, University of California, San Francisco, CA 94158., Alba DL; Diabetes Center, University of California, San Francisco, CA 94143.; Divisions of Endocrinology, Department of Medicine, University of California, San Francisco, CA 94143., Singh S; Divisions of Endocrinology, Department of Medicine, University of California, San Francisco, CA 94143., Koliwad S; Diabetes Center, University of California, San Francisco, CA 94143.; Divisions of Endocrinology, Department of Medicine, University of California, San Francisco, CA 94143., Lizama CO; Cardiovascular Research Institute, University of California, San Francisco, CA 94158., Atabai K; Cardiovascular Research Institute, University of California, San Francisco, CA 94158.; Diabetes Center, University of California, San Francisco, CA 94143.; Lung Biology Center, University of California, San Francisco, CA 94158.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Jun 01. Date of Electronic Publication: 2023 Jun 01.
DOI:	10.1101/2023.05.30.542928
Abstrakt:	The role of integrins in regulating insulin signaling is incompletely understood. We have previously shown that binding of the integrin ligand milk fat globule epidermal growth factor like 8 (MFGE8) to the αvβ5 integrin promotes termination of insulin receptor signaling in mice. Upon ligation of MFGE8, β5 complexes with the insulin receptor beta (IRβ) in skeletal muscle resulting in dephosphorylation of IRβ and reduction of insulin-stimulated glucose uptake. Here we investigate the mechanism by which the interaction between β5 and IRβ impacts IRβ phosphorylation status. We show that β5 blockade inhibits and MFGE8 promotes PTP1B binding to and dephosphorylation of IRβ resulting in reduced or increased insulin-stimulated myotube glucose uptake respectively. The β5-PTP1B complex is recruited by MFGE8 to IRβ leading to termination of canonical insulin signaling. β5 blockade enhances insulin-stimulated glucose uptake in wild type but not Ptp1b KO mice indicating that PTP1B functions downstream of MFGE8 in modulating insulin receptor signaling. Furthermore, in a human cohort, we report serum MFGE8 levels correlate with indices of insulin resistance. These data provide mechanistic insights into the role of MFGE8 and β5 in regulating insulin signaling. Competing Interests: Conflict of interest None
Databáze:	MEDLINE
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