MFGE8 inhibits insulin signaling through PTP1B

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 v{beta}5 integrin promotes termination of insulin receptor signaling in mice. Upon ligation of MFGE8, {beta}5 complexes with the insulin receptor beta (IR{beta}) in skeletal muscle resulting in dephosphorylation of IR{beta} and reduction of insulin-stimulated glucose uptake. Here we investigate the mechanism by which the interaction between {beta}5 and IR{beta} impacts IR{beta} phosphorylation status. We show that {beta}5 blockade inhibits and MFGE8 promotes PTP1B binding to and dephosphorylation of IR{beta} resulting in reduced or increased insulin-stimulated myotube glucose uptake respectively. The {beta}5-PTP1B complex is recruited by MFGE8 to IR{beta} leading to termination of canonical insulin signaling. {beta}5 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 {beta}5 in regulating insulin signaling.