IL-6 is a pleiotropic cytokine with important role in immune regulation, hematopoiesis, inflammation and oncogenesis. IL-6-type cytokines exert their action via the signal transducer gp130 that associates with IL6R in a cooperative manner to form a hexameric signal transducing complex, capable of activating the down stream mediators of this signaling pathway. This mechanism of signal transduction is shared by other members of the IL-6 type cytokines like IL-11, leukaemia inhibitory factor, oncostatin M, ciliary neurotrophic factor and cardiotrophin-1 that use gp130 as a common subunit of the signal transducing complex. IL-6 stimulation leads to the activation of JAK/STAT pathway. Both STAT1 and STAT3 are phosphorylated and are able to form homo- and heterodimers after activation leading to their nuclear localization and subsequent regulation of transcription of respective target genes. SHP-2 is one of the ubiquitous tyrosine phosphatases and IL-6 stimulation leads to the SHP2-dependent activation of MAPKs, it also links the Grb2-SOS complex and Gab1 to gp130. Phosphorylated Gab1 acts as an adapter and is involved in the indirect association of SHP-2 and PI-3 kinase. Downstream activation of Vav1, Rac-1 and MAP2K4 is necessary for the IL-6-mediated STAT3 phosphorylation and transactivation to accomplish its effects. STAT3 is also phosphorylated by PKCD and it causes inhibition of STAT3 DNA binding and transcriptional activity. PTPN11 and SOCS3 exert inhibitory function and thus lead to down regulation of the signaling cascade. Please access this pathway at [http://www.netpath.org/netslim/IL_6_pathway.html NetSlim] database. If you use this pathway, please cite the following paper: Kandasamy, K., Mohan, S. S., Raju, R., Keerthikumar, S., Kumar, G. S. S., Venugopal, A. K., Telikicherla, D., Navarro, J. D., Mathivanan, S., Pecquet, C., Gollapudi, S. K., Tattikota, S. G., Mohan, S., Padhukasahasram, H., Subbannayya, Y., Goel, R., Jacob, H. K. C., Zhong, J., Sekhar, R., Nanjappa, V., Balakrishnan, L., Subbaiah, R., Ramachandra, Y. L., Rahiman, B. A., Prasad, T. S. K., Lin, J., Houtman, J. C. D., Desiderio, S., Renauld, J., Constantinescu, S. N., Ohara, O., Hirano, T., Kubo, M., Singh, S., Khatri, P., Draghici, S., Bader, G. D., Sander, C., Leonard, W. J. and Pandey, A. (2010). NetPath: A public resource of curated signal transduction pathways. <i>Genome Biology</i>. 11:R3. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP364 CPTAC Assay Portal] d90 IL-6 stimulates the tyrosine phosphorylation of Gab1. Gab1 further forms a complex with SHP-2 and the p85 subunit of PI3 kinase in HepG2 cells. IL-6 receptor stimulation induces the phosphorylation of MEK1 in various cells. IL-6 receptor stimulation induces the phosphorylation and activation of ERK1 in AF-10 B cell line,LNCaP cells and human granulosa cells,ES cell line,E14TG2a respectively. IL-6 receptor stimulation induces the phosphorylation of SOS1 in multiple myeloma cells. IL-6 receptor stimulation induces the phosphorylation of MAP2K2 in multiple myeloma cells. IL-6 stimulates the phosphorylation and activation of protein kinase C delta in HepG2 cells. IL-6 receptor stimulation leads to HCK mediated tyrosine phosphorylation of GAB1 in HepG2 and MM cells. IL-6 receptor stimulation induces the phosphorylation and activation of ERK2 in AF-10 B cell line,LNCaP cells and human granulosa cells,ES cell line,E14TG2a respectively. IL-6 receptor stimulation leads to activation and tyrosine phosphorylation of HCK in LP-1 human multiple myeloma cell line. IL-6 receptor stimulation induces phosphorylation of AKT1 at Ser473 residue in MM.1S cells. IL-6 stimulation induces the GDP to GTP exchange of RAC1 with the association of VAV1. IL-6 stimulation induces the phosphorylation of STAT3 in various cells such as HUVECs, neuronal mouse cells, C57BL/6 mouse embryos, trophoblast cells, MM cell lines, myeloma cells, human breast epithelial cells and fibroblasts. The phosphorylation of STAT3 is observed at Tyr 705 as well as Ser 727 in these studies. IL-6 receptor stimulation induces the phosphorylation of VAV1 in HepG2 cells. IL-6 receptor stimulation induces phosphorylation of STAT1 at Tyr 701 in MM cells. IL-6 treatment induces the interaction of SOCS3 with IL6ST phosphorylated at Tyr 759 and represses IL-6 signaling. IL-6 stimulates the tyrosine phosphorylation of Gab1. Gab1 further forms a complex with SHP-2 and the p85 subunit of PI3 kinase in HepG2 cells. PTPN11 interats with gp130 phosphorylated at Tyr 759 upon IL6 stimulation in 2fTGH human fibrosarcoma and HepG2 cell lines. IL-6 stimulation induces the phosphorylation and activation of STAT1 and STAT3 and its subsequent heterodimerisation in murine Ba/F3 cells IL-6 receptor stimulation induces the phosphorylation of MKK4 which mediates the phosphorylation of PKC delta in HepG2 cells. IL-6 induces tyrosine phosphorylation of p52Shc and its interaction with Grb2 in AF10 cells, LP-1 multiple myeloma cell line and DeFew cells. IL-6 stimulation induces the interaction of p52Shc with phosphorylated gp130 in AF10 cells and DeFew-IL-6R/gp130 cells. IL-6 stimulation induces the phosphorylation of STAT3 at Ser 705 and subsequently its homodimerization in COS-7 cells and murine Ba/F3 cells. IL-6 stimulates the interaction of VAV1 with RAC1 in HepG2 cells. IL-6 stimulation induces the activation of HCK and its association with gp130 in LP-1 cells. IL-6 receptor stimulation induced the phosphorylation of p70S6K at Ser411, Thr421/Ser424, and Thr389 residues in AF-10 cells. STAT3 interacts with HDAC 1 which down-regulate IL-6-induced hAGT transactivation. IL-6 induces an increase in the autophosphorylation activity of TYK2 in undifferentiated ES cells. 20067622 PubMed NetPath: a public resource of curated signal transduction pathways. Genome Biol 2010 Kandasamy K Mohan SS Raju R Keerthikumar S Kumar GS Venugopal AK Telikicherla D Navarro JD Mathivanan S Pecquet C Gollapudi SK Tattikota SG Mohan S Padhukasahasram H Subbannayya Y Goel R Jacob HK Zhong J Sekhar R Nanjappa V Balakrishnan L Subbaiah R Ramachandra YL Rahiman BA Prasad TS Lin JX Houtman JC Desiderio S Renauld JC Constantinescu SN Ohara O Hirano T Kubo M Singh S Khatri P Draghici S Bader GD Sander C Leonard WJ Pandey A Interleukin mediated signaling pathway PW:0000512 Pathway Ontology interleukin-6 signaling pathway PW:0000516 Pathway Ontology