Integrin αVβ3 Contains a Cell Surface Receptor Site for Thyroid Hormone that Is Linked to Activation of Mitogen-Activated Protein Kinase and Induction of Angiogenesis

Integrin αVβ3 is a heterodimeric plasma membrane protein whose several extracellular matrix protein ligands contain an RGD recognition sequence. This study identifies integrin αVβ3 as a cell surface receptor for thyroid hormone [l-T4 (T4)] and as the initiation site for T4-induced activation of intracellular signaling cascades. Integrin αVβ3 dissociably binds radiolabeled T4 with high affinity, and this binding is displaced by tetraiodothyroacetic acid, αVβ3 antibodies, and an integrin RGD recognition site peptide. CV-1 cells lack nuclear thyroid hormone receptor, but express plasma membrane αVβ3; treatment of these cells with physiological concentrations of T4 activates the MAPK pathway, an effect inhibited by tetraiodothyroacetic acid, RGD peptide, and αVβ3 antibodies. Inhibitors of T4 binding to the integrin also block the MAPK-mediated proangiogenic action of T4. T4-induced phosphorylation of MAPK is inhibited by small interfering RNA knockdown of αV and β3. These findings suggest that T4 binds to αVβ3 near the RGD recognition site and show that hormone-binding to αVβ3 has physiological consequences.