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

Stephana Carelli, Anna Maria Di Giulio, Simona Paratore, Silvano Bosari, Alfredo Gorio

Research output: Contribution to journalArticlepeer-review

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-coatedvescicles 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 NH4Cl. 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.

Original languageEnglish
Pages (from-to)354-362
Number of pages9
JournalJournal of Cellular Physiology
Volume208
Issue number2
DOIs
Publication statusPublished - Aug 2006

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

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