Role of JAK family kinases in IL-6-type Cytokine Signaling

Janus kinases (JAK) are a family of intracellular protein tyrosine kinases of 120- 140 kDa. The JAK family includes JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2). While the expression of JAK1, JAK2 and TYK2 is ubiquitous, JAK3 is expressed predominantly in hematopoetic cells. IL-6-type cytokines Which include IL-6, IL-11, LIF, OSM, CNTF and CT-1 are known to use JAKs in their signal transduction pathways. The IL-6-type cytokines are grouped together based on their use of the common receptor subunit gp130 for signal transduction. As a consequence, these cytokines elicit similar and overlapping physiological responses.The IL-6 receptor complex consists of two subunits of gp130 and one of IL-6R. JAK1, JAK2 and TYK2 are associated with gp130. IL-6 binding triggers heterodimerization of gp130 and IL-6R subunits followed by tyrosine phosphorylation and activation of JAKs and phosphorylation of the signal transducing subunit gp130. JAK1 then tyrosine phosphorylates STAT3 which dissociates from the receptor, dimerizes and translocates to the nucleus where it binds to enhancer sequences of IL-6 target genes. SOCS-1 is an inhibitor of JAK1, JAK2 and TYK2 while SHP-2 inhibits JAK1 thus inhibiting IL-6 signaling.OSM binds to and activates a heterodimeric receptor which consists of one subunit each of gp130 and OSMR. OSM binding results in the activation and tyrosine phosphorylation in JAK1, JAK2 and TYK2 and the phosphorylation of OSMR and gp130. JAK phosphorylation in turn triggers the phosphorylation of STAT1, STAT3 and STAT5 which homo/heterodimerize and translocate to the nucleus. JAK1 has been shown to specifically phosphorylate Tyr861 in OSMR leading to the activation of stress-activated MAP kinases (p38MAPK and JNK) and ERK signaling pathways. Downregulation of OSMR signaling occurs via induction of the feedback inhibitor SOCS3 which binds both gp130 and JAK1.