Abstract
Insulin‐like growth factor‐I receptor (IGF‐IR) is often overexpressed in malignant tumors, and is involved in the establishment and maintenance of malignant phenotypes. Tyrosine kinase receptor endocytosis is commonly triggered by ligand binding and occurs via clathrin‐coated vescicles that transfer the receptor to the lysosome system for degradation. Our study aims at the evaluation of the mechanisms involved in IGF‐IR downregulation in neoplastic (Npl) and non‐neoplastic (non‐Npl) cells. Exposure to insulin‐like growth factor‐I (IGF‐I) of human lung adenocarcinoma cell lines (A549 and H1299) triggers IGF‐IR ubiquitination and internalization processes that require energy and are preceded by the phosphorylation of receptor tyrosines. Differently from other plasma membrane substrates of the ubiquitin system, IGF‐IR is degraded mostly by the proteasome in these tumor cell lines. The degradation is inhibited by lactacystin and unaffected by lysosomal inhibitors such as bafilomycin A1 and NH~4~Cl. IGF‐IR is processed in a similar manner also in fresh specimens of human lung tumors, while it requires active lysosomal functions in non‐Npl human lung tissues. These results suggest that the degradation routes of ubiquitinated IGF‐IR diverge in normal and Npl cells, and further support the involvement of IGF‐IR signaling in cancer. Such a different route for IGF‐IR processing might take place sometime during development, since both proteasome and lysosome pathways are active in fetal lung human fibroblasts, IMR90 cells. J. Cell. Physiol. 208: 354–362, 2006. © 2006 Wiley‐Liss, Inc.