IL6 signaling pathway (Homo sapiens)

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1IL-6 signaling pathwayMAP2K1PIL6STAT3GRB2MAPK3PSTAT1SOS1PMAP2K2PMAP2K4PPRKCDPGAB1PMAPK1PRPS6KB1HCKPAKT1PPIK3R1RAC1GTPGSK3BSHC1IL6RSTAT3PVAV1IL6STPJAK1PIK3R2JAK2SOCS3STAT1BADPTYK2PTPN11IL6RIL6IL6STSTAT regulated geneexpressionPRDM1STAT1MAP3K7STAT3STAT3IRF1BCL2L1STAT1STAT1CREBBPVIPSTAT3STAT1A2MCRPJUNBSTAT3HDAC1TIMP1STAT3NLKNCOA1STAT1EP300IL6STSTAT1AGTSTAT3NUCYNUCYNUCYMAP3K7ProteinProteinmRNALigandReceptorProteinProtein - protein dissociationEnzyme complexSmall moleculeInduced activationInhibitionAuto catalysisTransportPositive regulation of gene expressionLeads to through unknown mechanismNegative regulation of gene expressionTranslocation UbiquitinationDeubiquitinationSumoylationInduced catalysisProtein-protein interactionAcetylationDephosphorylationLEGENDPhosphorylationDeacetylationGolgi apparatusEndosomeNucleusMitochondrionDesumoylationMethylationDemethylationPalmitoylationCytoplasmECPlasma membraneMTEndoplasmic reticulumCYPMGONUExtracellularERENProteolytic cleavageMolecule


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 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. Genome Biology. 11:R3.

Proteins on this pathway have targeted assays available via the CPTAC Assay Portal

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Ontology Terms



  1. 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; ''NetPath: a public resource of curated signal transduction pathways.''; Genome Biol, 2010 PubMed Europe PMC Scholia


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121718view15:16, 26 February 2022EweitzModified title
120715view01:04, 24 December 2021EweitzStandardize font, weight, case
115943view08:20, 21 March 2021EgonwCopied the NetPath paper into the literature list
115929view08:07, 21 March 2021EgonwModified description
108327view21:09, 6 December 2019L DupuisConverted interactions to graphical lines in legend
106597view19:35, 10 September 2019KhanspersModified description
105508view06:00, 8 August 2019KhanspersModified description
89832view12:08, 6 October 2016MkutmonModified description
83783view15:44, 4 December 2015SusanChange ID of A2M
79962view13:38, 28 April 2015Zariannotated MAP3K7 gene
78561view10:31, 7 January 2015MaintBotadded missing graphIds
73871view14:01, 26 February 2014Joppe014connected lines; created complexes
73870view13:55, 26 February 2014Joppe014Periodical save, work in progress
73869view13:45, 26 February 2014Joppe014Periodical save, work in progress
73868view13:35, 26 February 2014Joppe014Periodical save, work in progress
73867view13:09, 26 February 2014Joppe014Periodical save, work in progress
73866view12:58, 26 February 2014Joppe014Periodical save, work in progress
72134view08:05, 25 October 2013Mkutmonadded datasource for "GAB1" and "IL6ST"
67384view10:45, 26 June 2013Christine ChichesterOntology Term : 'interleukin-6 signaling pathway' added !
63213view20:59, 8 May 2013MaintBotUpdating gpml version
48439view14:40, 24 May 2012NetPathModified description
44848view09:47, 6 October 2011MartijnVanIerselOntology Term : 'Interleukin mediated signaling pathway' added !
44627view18:07, 22 September 2011KhanspersUpdating content to NetSlim
44109view20:32, 24 August 2011KhanspersReverted to version '23:40, 1 March 2011' by Khanspers
44050view23:52, 22 August 2011KhanspersModified description
44049view23:51, 22 August 2011KhanspersUpdating pathway from NetSlim
41147view23:40, 1 March 2011MaintBotRemoved redundant pathway information and comments
35645view21:35, 12 February 2010KhanspersModified description
28142view23:57, 27 January 2009KhanspersChanged name
21441view11:31, 14 November 2008MaintBot[[Pathway:Homo sapiens:IL-6 NetPath 18]] moved to [[Pathway:WP364]]: Moved to stable identifier
8188view13:46, 7 January 2008MaintBot[[Pathway:Human:IL-6 NetPath 18]] moved to [[Pathway:Homo sapiens:IL-6 NetPath 18]]: Renaming species
7714view16:12, 18 December 2007MaintBotfixed category names
7253view12:41, 4 November 2007MaintBotAdded categories to GPML
6339view22:18, 22 May 2007A.Pandeygpml file for [[Human:IL-6_NetPath_18]]

External references


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NameTypeDatabase referenceComment
A2MProteinENSG00000175899 (miRBase mature sequence)
AGTProtein183 (Entrez Gene)
AKT1Protein207 (Entrez Gene)
BADProtein572 (Entrez Gene)
BCL2L1Protein598 (Entrez Gene)
CREBBPProtein1387 (Entrez Gene)
CRPProtein1401 (Entrez Gene)
EP300Protein2063 (Entrez Gene)
GAB1Protein2549 (Entrez Gene) 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.
GRB2Protein2885 (Entrez Gene)
GSK3BProtein2932 (Entrez Gene)
HCKProtein3055 (Entrez Gene)
HDAC1Protein3065 (Entrez Gene)
IL6Protein3569 (Entrez Gene)
IL6RProtein3570 (Entrez Gene)
IL6STProtein3572 (Entrez Gene)
IRF1Protein3659 (Entrez Gene)
JAK1Protein3716 (Entrez Gene)
JAK2Protein3717 (Entrez Gene)
JUNBProtein3726 (Entrez Gene)
MAP2K1Protein5604 (Entrez Gene)
MAP2K2Protein5605 (Entrez Gene)
MAP2K4Protein6416 (Entrez Gene)
MAP3K7Protein6885 (Entrez Gene)
MAPK1Protein5594 (Entrez Gene)
MAPK3Protein5595 (Entrez Gene)
NCOA1Protein8648 (Entrez Gene)
NLKProtein51701 (Entrez Gene)
PIK3R1Protein5295 (Entrez Gene)
PIK3R2Protein5296 (Entrez Gene)
PRDM1Protein639 (Entrez Gene)
PRKCDProtein5580 (Entrez Gene)
PTPN11Protein5781 (Entrez Gene)
RAC1Protein5879 (Entrez Gene)
RPS6KB1Protein6198 (Entrez Gene)
SHC1Protein6464 (Entrez Gene)
SOCS3Protein9021 (Entrez Gene)
SOS1Protein6654 (Entrez Gene)
STAT1Protein6772 (Entrez Gene)
STAT3Protein6774 (Entrez Gene)
TIMP1Protein7076 (Entrez Gene)
TYK2Protein7297 (Entrez Gene)
VAV1Protein7409 (Entrez Gene)
VIPProtein7432 (Entrez Gene)

Annotated Interactions

No annotated interactions

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