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Integrin _Vß₃ Contains a Cell Surface Receptor Site for Thyroid Hormone that Is Linked to Activation of Mitogen-Activated Protein Kinase and Induction of Angiogenesis

Ordway Research Institute (J.J.B., H.-Y.L., L.L., F.B.D., P.J.D.), Stratton Veterans Affairs Medical Center (H.-Y.L., F.B.D., P.J.D.), and Albany College of Pharmacy (S.N.M., S.M.), Albany, New York 12208; and The Wadsworth Center, New York State Department of Health (P.J.D.), Albany, New York 12201

Address all correspondence and requests for reprints to: Dr. Paul J. Davis, Ordway Research Institute, 150 New Scotland Avenue, Albany, New York 12208. E-mail: pdavis{at}ordwayresearch.org.

Integrin _Vß₃ is a heterodimeric plasma membrane protein whose several extracellular matrix protein ligands contain an RGD recognition sequence. This study identifies integrin _Vß₃ 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 _Vß₃ dissociably binds radiolabeled T₄ with high affinity, and this binding is displaced by tetraiodothyroacetic acid, _Vß₃ antibodies, and an integrin RGD recognition site peptide. CV-1 cells lack nuclear thyroid hormone receptor, but express plasma membrane _Vß₃; treatment of these cells with physiological concentrations of T₄ activates the MAPK pathway, an effect inhibited by tetraiodothyroacetic acid, RGD peptide, and _Vß₃ 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 _V and ß₃. These findings suggest that T₄ binds to _Vß₃ near the RGD recognition site and show that hormone-binding to _Vß₃ has physiological consequences.

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