Type 1 insulin-like growth factor receptor translocates to the nucleus of human tumor cells

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 cel...

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Published in:Cancer research (Chicago, Ill.) Vol. 70; no. 16; p. 6412
Main Authors: Aleksic, Tamara, Chitnis, Meenali M, Perestenko, Olga V, Gao, Shan, Thomas, Peter H, Turner, Gareth D, Protheroe, Andrew S, Howarth, Mark, Macaulay, Valentine M
Format: Journal Article
Language:English
Published: United States 15.08.2010
Subjects:
3T3 Cells
Animals
Breast Neoplasms - metabolism
Carcinoma, Renal Cell - metabolism
Cell Line, Tumor
Cell Membrane - metabolism
Cell Nucleus - metabolism
Humans
Immunohistochemistry
Kidney Neoplasms - metabolism
Male
Mice
Neoplasms - metabolism
Prostatic Neoplasms - metabolism
Protein Structure, Tertiary
Receptor, IGF Type 1 - metabolism
ISSN:1538-7445, 1538-7445
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Summary: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.
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ISSN:1538-7445
1538-7445
DOI:10.1158/0008-5472.CAN-10-0052