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The type 1 insulin-like growth factor receptor (IGF-1R) is a transmembrane glycoprotein composed of two extracellular alpha subunits and two beta subunits with tyrosine kinase activity. The IGF-1R is frequently upregulated in cancers and signals from the cell surface to promote proliferation and cell survival. Recent attention has focused on the IGF-1R as a target for cancer treatment. Here, we report that the nuclei of human tumor cells contain IGF-1R, detectable using multiple antibodies to alpha- and beta-subunit domains. Cell-surface IGF-1R translocates to the nucleus following clathrin-mediated endocytosis, regulated by IGF levels. The IGF-1R is unusual among transmembrane receptors that undergo nuclear import, in that both alpha and beta subunits traffic to the nucleus. Nuclear IGF-1R is phosphorylated in response to ligand and undergoes IGF-induced interaction with chromatin, suggesting direct engagement in transcriptional regulation. The IGF dependence of these phenomena indicates a requirement for the receptor kinase, and indeed, IGF-1R nuclear import and chromatin binding can be blocked by a novel IGF-1R kinase inhibitor. Nuclear IGF-1R is detectable in primary renal cancer cells, formalin-fixed tumors, preinvasive lesions in the breast, and nonmalignant tissues characterized by a high proliferation rate. In clear cell renal cancer, nuclear IGF-1R is associated with adverse prognosis. Our findings suggest that IGF-1R nuclear import has biological significance, may contribute directly to IGF-1R function, and may influence the efficacy of IGF-1R inhibitory drugs.

Original publication

DOI

10.1158/0008-5472.CAN-10-0052

Type

Journal article

Journal

Cancer Res

Publication Date

15/08/2010

Volume

70

Pages

6412 - 6419

Keywords

3T3 Cells, Animals, Breast Neoplasms, Carcinoma, Renal Cell, Cell Line, Tumor, Cell Membrane, Cell Nucleus, Humans, Immunohistochemistry, Kidney Neoplasms, Male, Mice, Neoplasms, Prostatic Neoplasms, Protein Structure, Tertiary, Receptor, IGF Type 1