Integrin alphaVbeta3 contains a cell surface receptor site for thyroid hormone that is linked to activation of mitogen-activated protein kinase and induction of angiogenesis.
Integrin alpha(V)beta(3) is a heterodimeric plasma membrane protein whose several extracellular matrix protein ligands contain an RGD recognition sequence. This study identifies integrin alpha(V)beta(3) as a cell surface receptor for thyroid hormone [L-T(4) (T(4))] and as the initiation site for T(4)-induced activation of intracellular signaling cascades. Integrin alpha(V)beta(3) dissociably binds radiolabeled T(4) with high affinity, and this binding is displaced by tetraiodothyroacetic acid, alpha(V)beta(3) antibodies, and an integrin RGD recognition site peptide. CV-1 cells lack nuclear thyroid hormone receptor, but express plasma membrane alpha(V)beta(3); treatment of these cells with physiological concentrations of T(4) activates the MAPK pathway, an effect inhibited by tetraiodothyroacetic acid, RGD peptide, and alpha(V)beta(3) antibodies. Inhibitors of T(4) binding to the integrin also block the MAPK-mediated proangiogenic action of T(4). T(4)-induced phosphorylation of MAPK is inhibited by small interfering RNA knockdown of alpha(V) and beta(3). These findings suggest that T(4) binds to alpha(V)beta(3) near the RGD recognition site and show that hormone-binding to alpha(V)beta(3) has physiological consequences.
Bergh
Joel J
JJ
Ordway Research Institute, 150 New Scotland Avenue, Albany, New York 12208, USA.
Lin
Hung-Yun
HY
Lansing
Lawrence
L
Mohamed
Seema N
SN
Davis
Faith B
FB
Mousa
Shaker
S
Davis
Paul J
PJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002460:Cell Line; D002642:Chick Embryo; D002522:Chlorocebus aethiops; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005347:Fibroblasts; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology; D011988:Receptors, Thyroid Hormone / Q000737:chemistry* / Q000502:physiology*; D013974:Thyroxine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D039302:Integrin alphaVbeta3; D008024:Ligands; D009842:Oligopeptides; D011988:Receptors, Thyroid Hormone; C047981:arginyl-glycyl-aspartic acid; D020928:Mitogen-Activated Protein Kinases; C011126:tetraiodothyroacetic acid; D013974:Thyroxine