GROWTH-INHIBITION SIGNALED THROUGH THE INTERLEUKIN-4 INTERLEUKIN-13 RECEPTOR COMPLEX IS ASSOCIATED WITH TYROSINE PHOSPHORYLATION OF INSULIN-RECEPTOR SUBSTRATE-1/

Induction of growth inhibition in human colorectal carcinoma cell line s by interleukin (IL)-4 and IL-13 was associated with the neophosphory lation of a 170 kDa cellular protein, identified as insulin receptor s ubstrate-1 (IRS-I) by immunoprecipitation. Tyrosine phosphorylation of IRS-I was also induced by insulin and insulin-like growth factor I. S ublines of colorectal carcinoma cells unresponsive to growth modulatio n by IL-4, IL-13 or insulin-like growth factor I-induced growth did no t phosphorylate IRS-1. A functional, multimeric IL-4 receptor complex was present on all carcinoma cell lines with a subunit composition of 65 kDa, 75 kDa and the previously characterized 130 kDa band as demons trated by affinity cross-linking with I-125-labelled IL-4. The 65 kDa subunit is novel whereas the 75 kDa band represents the common IL-2 re ceptor gamma-chain. The novel 65 kDa receptor was present as a double band and bound primarily I-125-labelled IL-13, The present study demon strates the involvement of a novel chain other than the gamma-chain in the receptor complexes of IL-4 and IL-13 and post-receptor tyrosine p hosphorylation of IRS-1. The association of IRS-1 with growth inhibito ry signals in carcinoma cells suggests a novel mechanism of tumour gro wth control.