DIFFERENTIATION AND GROWTH ARREST SIGNALS ARE GENERATED THROUGH THE CYTOPLASMIC REGION OF GP130 THAT IS ESSENTIAL FOR STAT3 ACTIVATION

Interleukin-6 (IL-6) induces growth arrest and macrophage differentiat ion through its receptor in a murine myeloid leukaemic cell line, M1, although it is largely unknown how the IL-6 receptor generates these s ignals. By using chimeric receptors consisting of the extracellular do main of growth hormone receptor and the transmembrane and cytoplasmic domain of gp130 with progressive C-terminal truncations, we showed tha t the membrane-proximal 133, but not 108, amino acids of gp130 could g enerate the signals for growth arrest, macrophage differentiation, dow n-regulation of c-myc and c-myb, induction of junB and IRF1 and Stat3 activation, Mutational analysis of this region showed that the tyrosin e residue with the YXXQ motif was critical not only for Stat3 activati on but also for growth arrest and differentiation, accompanied by down -regulation of c-myc and c-myb and immediate early induction of junB a nd IRF1. The tight correlation between Stat3 activation and other IL-6 functions was further observed in the context of the full-length cyto plasmic region of gp130. The results suggest that Stat3 plays an essen tial role in the signals for growth arrest and differentiation.