Degradation of insulin-like growth factor-I receptor occurs via ubiquitin-proteasome pathway in human lung cancer cells.

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.

• Authors: Stephana Carelli, Anna Maria Di Giulio, Simona Paratore, Silvano Bosari, Alfredo Gorio
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 208 Issue 2 Pg. 354-62 (Aug 2006) ISSN: 0021-9541 [Print] United States
• PMID: 16619240 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cysteine Proteinase Inhibitors
• Ubiquitin
• lactacystin
• Tyrosine
• Receptor, IGF Type 1
• Proteasome Endopeptidase Complex
• Acetylcysteine

Topics

• Acetylcysteine (analogs & derivatives, pharmacology)
• Cell Line
• Cell Line, Tumor
• Cysteine Proteinase Inhibitors (pharmacology)
• Down-Regulation
• Humans
• Kinetics
• Lung Neoplasms (enzymology, genetics, metabolism, pathology)
• Phosphorylation
• Proteasome Endopeptidase Complex (metabolism)
• Receptor, IGF Type 1 (antagonists & inhibitors, chemistry, metabolism)
• Tyrosine (chemistry)
• Ubiquitin (metabolism)