Integrin α_Vβ₃ contains a cell surface receptor site for thyroid hormone that is linked to activation of mitogen-activated protein kinase and induction of angiogenesis

Integrin α_Vβ₃ is a heterodimeric plasma membrane protein whose several extracellular matrix protein ligands contain an RGD recognition sequence. This study identifies integrin α _Vβ₃ as a cell surface receptor for thyroid hormone [L-T₄ (T₄)] and as the initiation site for T ₄-induced activation of intracellular signaling cascades. Integrin α_Vβ₃ dissociably binds radiolabeled T ₄ with high affinity, and this binding is displaced by tetraiodothyroacetic acid, α_Vβ₃ antibodies, and an integrin RGD recognition site peptide. CV-1 cells lack nuclear thyroid hormone receptor, but express plasma membrane α_Vβ ₃; treatment of these cells with physiological concentrations of T₄ activates the MAPK pathway, an effect inhibited by tetraiodothyroacetic acid, RGD peptide, and α_Vβ ₃ antibodies. Inhibitors of T₄ binding to the integrin also block the MAPK-mediated proangiogenic action of T₄. T ₄-induced phosphorylation of MAPK is inhibited by small interfering RNA knockdown of α_V and β₃. These findings suggest that T₄ binds to α_Vβ₃ near the RGD recognition site and show that hormone-binding to α _Vβ₃ has physiological consequences.