TRANSMEMBRANE DOMAIN OF GP130 CONTRIBUTES TO INTRACELLULAR SIGNAL-TRANSDUCTION IN HEPATIC CELLS

Interleukin-6 (IL-6) induces the expression of acute phase plasma prot ein genes in hepatic cells through the action of gp130, the signal-tra nsducing subunit of the IL-6 receptor, To identify whether the transme mbrane domain of gp130 is required for signaling function, cytoplasmic forms of gp130 were constructed that consisted of the tetramerizing N -terminal domain of Bcr linked to the transmembrane and cytoplasmic do mains of gp130 (Bcr/gp130) or just to the cytoplasmic domain of gp130 (Bcr/gp130 Delta TM), The expression and function of both constructs w ere determined in transiently transfected COS-1 and HepG2 cells, Bcr/g p130 is capable of interacting with JAK1, JAK2, and TYK2; is constitut ively active; and induces gene expression through IL-6-responsive elem ents, In contrast, Bcr/gp130 Delta TM, while expressed at a higher lev el than Bcr/gp130 and still able to interact with JAK1, is ineffective in recruiting the endogenous signal transduction pathways for inducin g gene expression, However, Bcr/gp130 Delta TM initiates par tial sign aling in the presence of overexpressed JAK1 and TYK2, but not JAK2. Th e data suggest that the transmembrane domain of gp130 is necessary for signal transduction and determines the interaction with members of th e Janus kinase family.