IL-6 signaling pathway (WP135)

Rattus norvegicus

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.


Akhilesh Pandey , Kristina Hanspers , Christine Chichester , Jonathan Mélius , Martina Summer-Kutmon , Egon Willighagen , Eric Weitz , and Alex Pico


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Rattus norvegicus



Pathway Ontology

interleukin-6 signaling pathway


Label Type Compact URI Comment
Ppp2r5e GeneProduct ncbigene:299147
Map3k7 GeneProduct ncbigene:313121
RGD1561602 GeneProduct ncbigene:497961
Stat3 GeneProduct ncbigene:25125
Stat1 GeneProduct ncbigene:25124
Hspca GeneProduct ncbigene:299331
Btk GeneProduct ncbigene:367901
Stat3 GeneProduct ncbigene:25125
Crebbp GeneProduct ncbigene:54244
Hspb1 GeneProduct ncbigene:24471
Ppp2r1a GeneProduct ncbigene:117281
Casp3 GeneProduct ncbigene:25402
Nfkb1 GeneProduct ncbigene:81736
Gab1 GeneProduct ncbigene:361388
Stat5b GeneProduct ncbigene:25126
Bad GeneProduct ncbigene:64639
Cebpb GeneProduct ncbigene:24253
Ar GeneProduct ncbigene:24208
Foxo1a GeneProduct ncbigene:84482
Prkcd GeneProduct ncbigene:170538
Hras GeneProduct ncbigene:293621
Cdk5r1 GeneProduct ncbigene:116671
Nfkb1 GeneProduct ncbigene:81736
Ptk2 GeneProduct ncbigene:25614
Il6ra GeneProduct ensembl:ENSRNOG00000020811
Tec GeneProduct ncbigene:84492
Ncoa1 GeneProduct ncbigene:313929
Stat1 GeneProduct ncbigene:25124
Map2k6 GeneProduct ncbigene:114495
Stat1 GeneProduct ncbigene:25124
Inppl1 GeneProduct ncbigene:65038
Stat3 GeneProduct ncbigene:25125
Ppp2r5d GeneProduct ensembl:ENSRNOG00000016849
Cdk5 GeneProduct ncbigene:140908
Mapt GeneProduct ensembl:ENSRNOG00000005133
Cebpb GeneProduct ncbigene:24253
Tyk2 GeneProduct ensembl:ENSRNOG00000032948
Sgk GeneProduct ncbigene:29517
Ppp2cb GeneProduct ncbigene:24673
Stat3 GeneProduct ncbigene:25125
Il6 GeneProduct ncbigene:24498
Grb2 GeneProduct ncbigene:81504
Ep300 GeneProduct ncbigene:170915
Ptpn11 GeneProduct ncbigene:25622
Ppp2r1b GeneProduct ncbigene:315648
Map2k1 GeneProduct ncbigene:170851
RGD1564385 GeneProduct ncbigene:361597
Gsk3b GeneProduct ncbigene:84027
Ppp2r3a GeneProduct ncbigene:363122
Mapk3 GeneProduct ncbigene:50689
Mapk1 GeneProduct ncbigene:116590
Akt1 GeneProduct ncbigene:24185
RGD1561201 GeneProduct ncbigene:302415
Rps6kb1 GeneProduct ncbigene:83840
Erbb2 GeneProduct ncbigene:24337
Jak1 GeneProduct ncbigene:84598
Pik3r1 GeneProduct ncbigene:25513
Mapk14 GeneProduct ncbigene:81649
Il6ra GeneProduct ensembl:ENSRNOG00000020811
Raf1 GeneProduct ncbigene:24703
PPP2R5C GeneProduct ncbigene:691318
Hck GeneProduct ncbigene:25734
Ppp2ca GeneProduct ncbigene:24672
Vav1 GeneProduct ncbigene:25156
Jak2 GeneProduct ncbigene:24514
Rps6ka2 GeneProduct ncbigene:117269
Inpp5d GeneProduct ncbigene:54259
Stat1 GeneProduct ncbigene:25124
PPP2R3B GeneProduct ncbigene:682033
Gab2 GeneProduct ncbigene:84477
Ppp2r4 GeneProduct ncbigene:362102
Erbb3 GeneProduct ncbigene:29496
Fgr GeneProduct ncbigene:79113
Map3k4 GeneProduct ncbigene:308106
Foxo3a GeneProduct ncbigene:294515
Casp9 GeneProduct ncbigene:58918
Stat3 GeneProduct ncbigene:25125
Il6 GeneProduct ncbigene:24498
Ppp2r5b GeneProduct ncbigene:309179
Ppp2r5a GeneProduct ncbigene:312754
Ppp2r2c GeneProduct ensembl:ENSRNOG00000058202
Stat3 GeneProduct ncbigene:25125
Tnfrsf5 GeneProduct ncbigene:171369
Map3k7 GeneProduct ncbigene:313121
Hdac1 GeneProduct ncbigene:297893
Sos1 GeneProduct ncbigene:313845
Sgk GeneProduct ncbigene:29517
Eif2a GeneProduct ncbigene:502531
Mapk14 GeneProduct ncbigene:81649
Il6st GeneProduct ncbigene:25205
Stat5a GeneProduct ncbigene:24918
Jun GeneProduct ncbigene:24516
Daxx GeneProduct ncbigene:140926
Tcf1 GeneProduct ncbigene:24817
Fyn GeneProduct ncbigene:25150
Plcg1 GeneProduct ncbigene:25738
Rac1 GeneProduct ncbigene:363875
Cdk9 GeneProduct ncbigene:362110
RGD1565643 GeneProduct ncbigene:367786
Socs3 GeneProduct ncbigene:89829
Shc1 GeneProduct ncbigene:85385
Lyn GeneProduct ncbigene:81515
Pxn GeneProduct ncbigene:360820
Pik3r2 GeneProduct ncbigene:29741
Map2k2 GeneProduct ncbigene:58960
Mapk8 GeneProduct ncbigene:116554
Stat3 GeneProduct ncbigene:25125
Stat3 GeneProduct ncbigene:25125
Map2k4 GeneProduct ncbigene:287398
Ppp2r2a GeneProduct ncbigene:117104
Ptk2b GeneProduct ncbigene:50646
Fos GeneProduct ncbigene:314322
Rb1 GeneProduct ncbigene:24708
Ppp2r2b GeneProduct ncbigene:60660
Eif4ebp1 GeneProduct ncbigene:116636
Mapkapk2 GeneProduct ncbigene:289014
Eif4e GeneProduct ncbigene:117045
Il6st GeneProduct ncbigene:25205