Interleukin (IL)-6 and IL-6-type cytokines signal through the gp130/Jak/STAT signal transduction pathway. The key components involved are the signal transducing receptor subunit gp130, the Janus kinases Jak1, Jak2 and Tyk2, STAT1 and STAT3 of the family of signal transducers and activators of transcription, the protein tyrosine phosphatase SHP2 and the suppressors of cytokine signalling SOCS1, SOCS2 and SOCS3. Whereas considerable information has been accumulated concerning the time-course of activation for the individual signalling molecules, data on the availability of the proteins involved in IL-6-type cytokine signal transduction are scarce. Nevertheless, availability of these molecules, determined by the balance of protein synthesis and degradation, also influences IL-6-type cytokine signal transduction. Here, we present a comprehensive set of data on the halflives of the key molecules involved in the IL-6 signal transduction pathway. The turnover rates for the various proteins differ substantially. Three groups of signalling proteins can be discriminated: whereas the feedback inhibitors SOCS1, SOCS2 and SOCS3 are very short-lived, STAT1, STAT3 and SHP2 have an extremely slow turnover rate. Interestingly, the half-life of STAT3b, a splice variant of STAT3a, is reduced to almost 50% of the half-life of STAT3a. The Janus kinases Jak1, Jak2, Tyk2 and gp130 show intermediate half-lives. Our data imply that signalling components activated by post-translational modifications are long-lived whereas the activity of very short-lived proteins is regulated mainly at the transcriptional level.Keywords: half-life; interleukin-6; interleukin-6-type cytokines; protein turnover; signal transduction.Interleukin-6 (IL-6) is a multifunctional cytokine which is involved in the regulation of complex cellular processes including proliferation, differentiation and gene activation. Among others, it plays a crucial role during haematopoesis and liver-specific processes such as acute-phase protein synthesis and liver regeneration. IL-6 and IL-6-type cytokines signal through the glycoprotein (gp)130/Jak/STAT pathway [1]: IL-6 exerts its action via a surface receptor complex composed of the specific interleukin-6 receptor a-chain (IL-6R; gp80) and the common signal transducer gp130. Binding of IL-6 to its receptor induces dimerization of gp130 [2,3], activation of the gp130-associated protein tyrosine kinases of the Janus kinase family Jak1, Jak2 and Tyk2 and phosphorylation of gp130 at cytoplasmic tyrosine residues [4,5]. These phosphotyrosines serve as docking sites for SH2-domain containing proteins such as the signal transducers and activators of transcription (STATs) STAT1 [6], STAT3 [6,7] and the protein tyrosine phosphatase SHP2 [7] which themselves become subsequently tyrosine phosphorylated. Jak1 was found to be essential for gp130-, , and SHP2-phosphorylation [9]. The phosphorylated STAT factors form homo-or heterodimers, translocate into the nucleus and bind to enhancers of IL-6 inducible genes [10,11]. SHP2 is believed to ...