Nuclear monomeric integrin αv in cancer cells is a coactivator regulated by thyroid hormone

Thyroid hormone induces tumor cell and blood vessel cell proliferation via a cell surface receptor on heterodimeric integrin v3. We investigated the role of thyroid hormone-induced internalization of nuclear integrin v monomer. Physiological concentration of thyroxine (free T-4, 10(-10) M), but not 3,5,3-triiodo-l-thyronine (T-3), induced cellular internalization and nuclear translocation of integrin v monomer in human non-small-cell lung cancer (H522) and ovarian carcinoma (OVCAR-3) cells. T-4 did not complex with integrin v monomer during its internalization. The v monomer was phosphorylated by activated ERK1/2 when it heterodimerized with integrin 3 in vitro. Nuclear v complexed with transcriptional coactivator proteins, p300 and STAT1, and with corepressor proteins, NCoR and SMRT. Nuclear v monomer in T-4-exposed cells, but not integrin 3, bound to promoters of specific genes that have important roles in cancer cells, including estrogen receptor-, cyclooxygenase-2, hypoxia-inducible factor-1, and thyroid hormone receptor 1 in chromatin immunoprecipitation assay. In summary, monomeric v is a novel coactivator regulated from the cell surface by thyroid hormone for the expression of genes involved in tumorigenesis and angiogenesis. This study also offers a mechanism for modulation of gene expression by thyroid hormone that is adjunctive to the nuclear hormone receptor (TR)-T-3 pathway.Lin, H.-Y., Su, Y.-F., Hsieh, M.-T., Lin, S., Meng, M., London, D., Lin, C., Tang, H.-Y., Hwang, J., Davis, F. B., Mousa, S. A., and Davis, P. J. Nuclear monomeric integrin v in cancer cells is a coactivator regulated by thyroid hormone.