Janus kinase 3

Janus kinase 3
PDB rendering based on 1yvj.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1YVJ, 3LXK, 3LXL, 3PJC, 3ZC6, 4HVD, 4HVG, 4HVH, 4HVI, 4I6Q
Identifiers
Symbols	JAK3; JAK-3; JAK3_HUMAN; JAKL; L-JAK; LJAK
External IDs	OMIM: 600173 MGI: 99928 HomoloGene: 181 ChEMBL: 2148 GeneCards: JAK3 Gene
EC number	2.7.10.2
Gene Ontology Molecular function • protein tyrosine kinase activity • non-membrane spanning protein tyrosine kinase activity • protein binding • ATP binding Cellular component • cytosol • cytoskeleton • endomembrane system • membrane Biological process • negative regulation of dendritic cell cytokine production • protein phosphorylation • enzyme linked receptor protein signaling pathway • intracellular protein kinase cascade • tyrosine phosphorylation of STAT protein • STAT protein import into nucleus • peptidyl-tyrosine phosphorylation • B cell differentiation • negative regulation of interleukin-10 production • negative regulation of interleukin-12 production • interleukin-4-mediated signaling pathway • regulation of apoptotic process • T cell homeostasis • negative regulation of apoptotic process • innate immune response • negative regulation of FasL biosynthetic process • negative regulation of T-helper 1 cell differentiation • positive regulation of transcription from RNA polymerase II promoter • negative regulation of T cell activation • JAK-STAT cascade involved in growth hormone signaling pathway • regulation of T cell apoptotic process • negative regulation of thymocyte apoptotic process • response to interleukin-2 • response to interleukin-4 • response to interleukin-15 • response to interleukin-9 Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	3718	16453
Ensembl	ENSG00000105639	ENSMUSG00000031805
UniProt	P52333	Q62137
RefSeq (mRNA)	NM_000215	NM_001190830
RefSeq (protein)	NP_000206	NP_001177759
Location (UCSC)	Chr 19: 17.94 – 17.96 Mb	Chr 8: 71.68 – 71.69 Mb
PubMed search
This box: view talk edit

Tyrosine-protein kinase JAK3 is an enzyme that in humans is encoded by the JAK3 gene.^[1][2]

Janus kinases

Janus kinase 3 is a tyrosine kinase that belongs to the Janus family of kinases. Other members of the Janus family include JAK1, JAK2 and TYK2. Janus kinases (JAKs) are relatively large kinases of approximately 1150 amino acids with apparent molecular weights of 120-130 kDa.^[3] They are cytosolic tyrosine kinases that are specifically associated with cytokine receptors. Since cytokine receptor proteins lack enzymatic activity, they are dependent upon JAKs to initiate signaling upon binding of their ligands (e.g. cytokines). The cytokine receptors can be divided into five major subgroups based on their different domains and activation motifs. JAK3 is required for signaling of the type I receptors that use the common gamma chain (γc).

Function

In contrast to the relatively ubiquitous expression of JAK1, JAK2 and Tyk2, JAK3 is predominantly expressed in hematopoietic lineage such as NK cells, T cells and B cells^[3] and intestinal epithelial cells.^[5][6][7] JAK3 functions in signal transduction and interacts with members of the STAT (signal transduction and activators of transcription) family. JAK3 is predominantly expressed in immune cells and transduces a signal in response to its activation via tyrosine phosphorylation by interleukin receptors. Mutations that abrogate Janus kinase 3 function cause an autosomal SCID (severe combined immunodeficiency disease).^[8]

Jak3 interacts with actin-binding protein villin, thereby facilitating cytoskeletal remodeling and mucosal wound repair.^[7] Structural determinants that regulate the interactions between Jak3 and cytoskeletal proteins of the villin / gelsolin family have also been characterized. Functional reconstitution of kinase activity by recombinant Jak3 using Jak3-wt or villin/gelsolin-wt as substrate showed that Jak3 autophosphorylation was the rate-limiting step during interactions between Jak3 and cytoskeletal proteins. Kinetic parameters showed that phosphorylated (P) Jak3 binds to P-villin with a dissociation constant (K_d) of 23 nM and a Hill's coefficient of 3.7. Pairwise binding between Jak3 mutants and villin showed that the FERM domain of Jak3 was sufficient for binding to P-villin with a K_d of 40.0 nM. However, the SH2 domain of Jak3 prevented P-villin from binding to the FERM domain of nonphosphorylated protein. The intramolecular interaction between the FERM and SH2 domains of nonphosphorylated Jak3 prevented Jak3 from binding to villin and tyrosine autophosphorylation of Jak3 at the SH2 domain decreased these intramolecular interactions and facilitated binding of the FERM domain to villin. These demonstrate the molecular mechanism of interactions between Jak3 and cytoskeletal proteins where tyrosine phosphorylation of the SH2 domain acted as an intramolecular switch for the interactions between Jak3 and cytoskeletal proteins.^[5]

Sustained damage to the mucosal lining in patients with inflammatory bowel disease (IBD) facilitates translocation of intestinal microbes to submucosal immune cells leading to chronic inflammation. IL-2 plays a role in intestinal epithelial cell (IEC) homeostasis through concentration-dependent regulation of IEC proliferation and cell death. Activation by IL-2 led to tyrosine phosphorylation-dependent interactions between Jak3 and p52ShcA only at lower concentrations. Higher concentrations of IL-2 decreased the phosphorylation of Jak3, disrupted its interactions with p52ShcA, redistributed Jak3 to the nucleus, and induced apoptosis in IEC. IL-2 also induced dose-dependent downregulation of jak3-mRNA. Constitutive overexpression and mir-shRNA-mediated knockdown studies showed that expression of Jak3 was necessary for IL-2-induced proliferation of IEC. Additionally, IL-2-induced downregulation of jak3-mRNA was responsible for higher IL-2-induced apoptosis in IEC. Thus IL-2-induced mucosal homeostasis through posttranslational and transcriptional regulation of Jak3.^[6]

Since JAK3 expression is restricted mostly to hematopoietic cells, its role in cytokine signaling is thought to be more restricted than other JAKs. It is most commonly expressed in T cells and NK cells, but has been induced in other leukocytes, including monocytes. JAK3 is involved in signal transduction by receptors that employ the common gamma chain (γc) of the type I cytokine receptor family (e.g. IL-2R, IL-4R, IL-7R, IL-9R, IL-15R, and IL-21R).^[9] Mutations of JAK3 result in severe combined immunodeficiency (SCID). Mice that do not express JAK3 have T-cells and B-cells that fail to respond to many cytokines.^[10]

In addition to its well-known roles in T cells and NK cells, JAK3 has recently been found to mediate IL-8 stimulation in human neutrophils. IL-8 primarily functions to induce chemotaxis in neutrophils and lymphocytes, and JAK3 silencing severely inhibits IL-8-mediated chemotaxis.^[11]

Signal transduction model

Activation of JAK3 by cytokine receptors that contain the common gamma chain (γc)

JAK3 is activated only by cytokines whose receptors contain the common gamma chain (γc) subunit: IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. Cytokine binding induces the association of separate cytokine receptor subunits and the activation of the receptor-associated JAKs. In the absence of cytokine, JAKs lack protein tyrosine kinase activity. Once activated, the JAKs create docking sites for the STAT transcription factors by phosphorylation of specific tyrosine residues on the cytokine receptor subunits. STATs (signal transduction and activators of transcription) are members of a family of transcription factors, and they have src homology 2 (SH2) domains that allow them to bind to these phosphorylated tyrosine residues. After undergoing JAK-mediated phosphorylation, the STAT transcription factors dimerize, translocate to the nucleus, bind DNA at specific elements and induce expression of specific genes.^[3] Cytokine receptors selectively activate particular JAK-STAT pathways to induce transcription of different genes. IL-2 and IL-4 activate JAK1, JAK3 and STAT5.^[12]

Disease relevance

Activating mutations in JAK1, JAK2, and JAK3 have been identified as causes of hematological cancers, while inactivating mutations of JAK3 are known causes of immune deficiency.^[13] Mutations in the common gamma chain (γc) result in X-linked severe combined immunodeficiency (X-SCID). Since γc specifically associates with JAK3, mutations in JAK3 also result in SCID.^[14] Deficiency of JAK3 blocks signaling of the following cytokines and their effects:^[4]

• IL-2 - T cell proliferation and maintenance of peripheral tolerance
• IL-4 - differentiation of Th2 cells
• IL-7 - thymocyte development in the thymus
• IL-9 - survival signal for various hematopoietic cells
• IL-15 - NK cell development
• IL-21 - regulation of immunoglobulin class switching in B cells

Overall, JAK3 deficiency results in the phenotype of SCID characterized by T⁻B⁺NK⁻, which indicates the absence of T cells and NK cells.^[15] Although B cells are present, they are non-functional due to defective B cell activation and impaired antibody class switching.

Since JAK3 is required for immune cell development, targeting JAK3 could be a useful strategy to generate a novel class of immunosuppressant drugs. Moreover, unlike other JAKs, JAK3 is primarily expressed in hematopoietic cells, so a highly specific JAK3 inhibitor should have precise effects on immune cells and minimal pleiotropic defects.^[4] The selectivity of a JAK3 inhibitor would also have advantages over the current widely used immunosuppressant drugs, which have abundant targets and diverse side effects. A JAK3 inhibitor could be useful for treating autoimmune diseases, especially those in which a particular cytokine receptor has a direct role on disease pathogenesis. For example, signaling through the IL-15 receptor is known to be important in the development rheumatoid arthritis,^[16] and the receptors for IL-4 and IL-9 play roles in the development of allergic responses.^[17]

A selective JAK3 inhibitor, designated CP-690550, has been developed and shown promise in clinical trials. This drug has nanomolar potency against JAK3 and was shown to be effective in preventing transplant rejection in a nonhuman primate renal transplant model.^[4] CP-690550 also demonstrated immunosuppressive activity in phase I and II clinical trials of rheumatoid arthritis, psoriasis and organ transplant rejection.^[18] CP-690550 (Tofacitinib) is currently being investigated in phase III clinical trials by Pfizer for the treatment of rheumatoid arthritis.^[19]

Interactions

Janus kinase 3 has been shown to interact with CD247,^[20] TIAF1^[21] and IL2RG.^[22][23]

References

Further reading

External links

• Janus Kinase 3 at the US National Library of Medicine Medical Subject Headings (MeSH)

v t e PDB gallery 1yvj: Crystal structure of the Jak3 kinase domain in complex with a staurosporine analogue