The molecular regulation of Janus kinase (JAK) activation

Abstract

The Janus Kinase (JAK) family members serve essential roles as the intracellular signalling effectors of cytokine receptors. This family, comprising JAK1, JAK2, JAK3 and TYK2, was first described more than 20 years ago, but the complexities underlying their activation, regulation and pleiotropic signalling functions are still being explored. Here, we review the current knowledge of their physiological functions and the causative role of activating and inactivating JAK mutations in human diseases, including haematopoietic malignancies, immunodeficiency and inflammatory diseases. At the molecular level, recent studies have greatly advanced our knowledge of the structures and organisation of the component FERM-SH2, pseudokinase and kinase domains within the JAKs, the mechanism of JAK activation and, in particular, the role of the pseudokinase domain as a suppressor of the adjacent tyrosine kinase domain's catalytic activity. We also review recent advances in our understanding of the mechanisms of negative regulation exerted by the SH2 domain containing proteins, SOCS (Suppressors of Cytokine Signalling) proteins and Lnk. These recent advances highlight the diversity of regulatory mechanisms utilised by the JAK family to maintain signalling fidelity, and suggest alternative therapeutic strategies to complement existing ATP-competitive kinase inhibitors.

TYK2, a Candidate Gene for Type 1 Diabetes, Modulates Apoptosis and the Innate Immune Response in Human Pancreatic β-Cells

“…TYK2 was identified in the pathway analysis described above, and it plays a critical role in the intracellular signaling of type I IFNs via phosphorylation and activation of STAT proteins (14). Of note, type I IFNs play an important role in several autoimmune IFNb (E and K), and CXCL10 (F and L) was measured in the supernatants by ELISA.…”

“…Ingenuity Pathway Analysis of the type 1 diabetes candidate genes expressed in human pancreatic b-cells identified as the three top canonical pathways "interferon signaling," "role of JAK1, JAK2 and TYK2 in IFN signaling," and "role of pattern recognition receptors in recognition of bacteria and virus." TYK2, a key regulator of IFN signaling (14), was listed in three out of the four top canonical pathways identified, namely, "interferon signaling," "role of JAK1, JAK2 and TYK2 in IFN signaling," and "Tec kinase signaling." Furthermore, and in line with a previous bioinformatics prediction (15), BLCLs obtained from patients with genotype AA of the TYK2 SNP rs2304256 (the variant protective against type 1 diabetes) showed a trend for less marked IFNa-induced STAT1 phosphorylation, as compared with patients with genotype CC (Fig.…”

“…4). TYK2 is a member of the JAK family of kinases that transduce type I IFN signals by phosphorylating STAT proteins, such as STAT1 and STAT2 (14). PIC treatment induced a two-and fourfold increase in phospho-STAT2 and phospho-STAT1, respectively, and a nonsignificant trend toward higher expression of total STAT1 and STAT2 in dispersed human islet cells and EndoC-bH1 cells ( Fig.…”

“…These kinases play a critical role in the intracellular signaling of several cytokines and type I interferons (IFNs) through phosphorylation and activation of signal transducers and activators of transcription (STATs) (14). TYK2 has been associated with several autoimmune diseases, such as systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, and type 1 diabetes (15,16).…”

Jak3 is involved in CCR7-dependent migration and invasion in metastatic squamous cell carcinoma of the head and neck

“…It was reported that the tyrosine phosphorylation of the members of the Janus family of kinases, including Jak1, Jak2, Jak3 and tyrosine kinase 2 (Tyk2), may be involved in the occurrence and development of prostate and breast cancer (9). Specifically, it has been demonstrated that Jak3 is involved in dendritic cell maturation and migration via the CCR7-mediated signaling pathway (10,11).…”