Different protein turnover of interleukin‐6‐type cytokine signalling components

Abstract

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 ...

Biallelic deletion within 16p13.13 including SOCS‐1 in Karpas1106P mediastinal B‐cell lymphoma line is associated with delayed degradation of JAK2 protein

“…Immediately after the pulse, no significant differences of 35 S-incorporation into the total proteins of Karpas1106P and Ramos cells were measured, but newly synthesized JAK2 during the pulse period was clearly higher in Ramos cells than in Karpas1106P. Furthermore, the turnover of 35 S-JAK2 was strikingly protracted in Karpas1106P, whereas the half-life of JAK2 in Ramos cells corresponds to published data 19 ( Fig. 5).…”

Stimulation of Leukemia Inhibitory Factor Receptor Degradation by Extracellular Signal-regulated Kinase

“…3B). The smaller size protein likely represents immature, intracellular LIFR␣, analogous to the findings with gp130 (34). As shown in Fig.…”

“…1A). Treatment with monensin, which prevents the transfer of glycoproteins from the endoplasmic reticulum/Golgi ap-paratus to the plasma membrane (34), caused an accumulation of the lower form of the LIFR␣, suggesting a precursor-product relationship between the two forms ( Fig. 1D).…”

Downregulation of IL-6-induced STAT3 tyrosine phosphorylation by TGF-β1 is mediated by caspase-dependent and -independent processes

“…22,24,40 On the other hand, factors like IL-6 play an equally important role in the maintenance of the renewing pool of hematopoietic progenitor cells. 41,42 In the case of AML, the equilibrium between both positive and negative regulating factors might be disturbed, leading to a disruption in the negative control of cell proliferation. 43 The present study indicates that in a subset of AML blasts TGF-␤1 treatment causes apoptosis, resulting in degradation of JAK kinases involved in IL-6 signal transduction, as well as an apoptosis-unrelated event leading to a diminished JAK1 phosphorylation upon IL-6 stimulation.…”

“…This could then result in a reduced expression after 20 h of TGF-␤1 treatment because of the relative high turnover rate of at least the JAK kinases. 41 The reduction of proteins involved in cell cycle progression and survival might be an important cellular mechanism to support the apoptotic process. However, despite the prevention of TGF-␤1 and VP16-induced apoptosis and subsequent JAK protein degradation by the caspase inhibitor, a reduced IL-6-mediated STAT3 tyrosine phosphorylation after TGF-␤1 treatment was still present suggesting that additional factors must contribute to the attenuation of the IL-6 STAT3 signaling pathway by TGF-␤1.…”