We analysed the interaction of gp130, the common signaltransducing receptor chain of interleukin (IL)-6 type cytokines, with Jak1, the Janus family kinase which is crucial for signal transduction of this group of cytokines. With a truncated chimaeric IL-5Rβ-gp130 receptor expressed in COS-7 cells, we show that the membrane-proximal 69 amino acids are sufficient to mediate Jak1 binding and activation. Deletion of box2 drastically reduced binding of endogenous, but not of overexpressed, Jak1. Several point mutations in the membraneproximal region of gp130 (W652A, P671\P672A, F676A, Y683F, where W, A, P, F and Y are tryptophan, alanine, proline, phenylalanine and tyrosine) did not affect Jak1 association. However, stimulation of chimaeric receptors with the mutations P671\P672A and F676A in the interbox1\box2 region resulted in a reduced activation of STAT (signal transducer and activator of transcription) transcription factors. Most importantly, signal-

Leukaemia inhibitory factor (LIF) signals via a heterodimeric receptor complex comprised of the LIF receptor (LIFR) and the interleukin (IL)-6 signal transducer gp130. Upon binding to its cognate receptor LIF is internalized. In this study, we show that the LIFR is endocytosed independently of gp130. By using a heterochimaeric receptor system we identified a dileucine-based internalization motif within the cytoplasmic domain of the LIFR. Our findings suggest that a heterodimeric LIFR/gp130 complex and homodimeric gp130/gp130 complex are endocytosed via distinct internalization signals.