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 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.
Aleksic
Tamara
T
Department of Cellular Pathology, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
Chitnis
Meenali M
MM
Perestenko
Olga V
OV
Gao
Shan
S
Thomas
Peter H
PH
Turner
Gareth D
GD
Protheroe
Andrew S
AS
Howarth
Mark
M
Macaulay
Valentine M
VM
D016475:3T3 Cells; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000378:metabolism; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism; D017434:Protein Structure, Tertiary; D017526:Receptor, IGF Type 1 / Q000378:metabolism*
D017526:Receptor, IGF Type 1