Inhibition of endosomal insulin-like growth factor-I processing by cysteine proteinase inhibitors blocks receptor-mediated functions

被引:41
作者
Navab, R
Chevet, E
Authier, F
Di Guglielmo, GM
Bergeron, JJM
Brodt, P
机构
[1] McGill Univ, Royal Victoria Hosp, Ctr Hlth, Dept Surg, Montreal, PQ H3A 1A4, Canada
[2] McGill Univ, Dept Anat & Cell Biol, Montreal, PQ H3A 2B2, Canada
[3] Fac Pharm Paris 11, INSERM, U510, F-92296 Chatenay Malabry, France
关键词
D O I
10.1074/jbc.M100019200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The receptor for the type 1 insulin-like growth factor (IGF-D has been implicated in cellular transformation and the acquisition of an invasive/metastatic phenotype in various tumors. Following ligand binding, the IGF-I receptor is internalized, and the receptor ligand complex dissociates as the ligand is degraded by endosomal proteinases, In the present study we show that the inhibition of endosomal IGF-I-degrading enzymes in human breast and murine lung carcinoma cells by the cysteine proteinase inhibitors, E-64 and CA074-methyl ester, profoundly altered receptor trafficking and signaling. In treated cells, intracellular ligand degradation was blocked, and although the receptor and two substrates, Shc and Insulin receptor substrate, mere hyperphosphorylated on tyrosine, IGF-I-induced DNA synthesis, anchorage-independent growth, and matrix metalloproteinase synthesis were inhibited. The results suggest that ligand processing by endosomal proteinases is a key step in receptor signaling and function and a potential target for therapy.
引用
收藏
页码:13644 / 13649
页数:6
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