Figure 2 Signalling downstream of the IL-6 receptor

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Figure 2 Signalling downstream of the IL-6 receptor Figure 2 | Signalling downstream of the IL-6 receptor. JAK proteins bind to the Box 1 and Box 2 domains in the intracellular portion of IL-6 receptor subunit-β (gp130). This leads to JAK-mediated phosphorylation of gp130 at several tyrosine residues, including four C-terminal residues that serve as docking sites for STAT3. Once bound to gp130, STAT3 is phosphorylated by JAKs at tyrosine 705, leading to STAT3 dimerization and nuclear translocation, followed by STAT3-mediated transcription of target genes. The figure shows signalling initiated by classic signalling. Trans-signalling pathways initiate downstream signalling in the same fashion. Tyrosine phosphorylation of STAT3 can also be induced by other oncogenic proteins, including SRC and BCR–ABL1. IL-6/JAK/STAT3 signalling is negatively regulated by a number of mechanisms. Suppressor of cytokine signalling (SOCS) 1 and SOCS3 bind to and inhibit the kinase activity of JAKs. SOCS3 is a STAT3 target gene; following transcription, SOCS3 then acts as a component of a negative-feedback loop that maintains tight regulation of this pathway. The following phosphatases also have a role in the negative regulation of this pathway: tyrosine-protein phosphatase non-receptor type 6 (SHP1; also known as PTPN6); tyrosine-protein phosphatase non-receptor type 11 (SHP2); dual specificity protein phosphatase 22 (DUSP22); receptor-type tyrosine-protein phosphatase-δ (PTPRD); receptor-type tyrosine-protein phosphatase T (PTPRT); tyrosine-protein phosphatase non-receptor type 1 (PTPN1); tyrosine-protein phosphatase non-receptor type 2 (PTPN2). Protein inhibitor of activated STAT3 (PIAS3), an E3 SUMO protein ligase, as well as PDZ and LIM domain protein 2 (PDLIM2), an ubiquitin E3 ligase, are additional endogenous proteins that inhibit STAT3 by mediating STAT3 degradation. The expression of PIAS3 and PDLIM2 can be inhibited by oncogenic microRNAs (miRNAs): miR-18a targets PIAS3, whereas miR-221 and miR-222 target PDLIM2. Another miRNA, miR-551b-3p, promotes STAT3 gene expression. Other miRNAs act to negatively regulate the IL-6/JAK/STAT3 pathway: expression of IL6R is inhibited by miR-218 and miR-34a, while STAT3 expression is inhibited by miR-17-5p, miR-20a, and miR-124. Johnson, D. E. et al. (2018) Targeting the IL‑6/JAK/STAT3 signalling axis in cancer Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2018.8