Role of JAK1, JAK2 and TYK2 in Interferon Signaling


Pathway Description

The family of Janus kinase (JAK) tyrosine kinases consists of 4 members: JAK1, JAK2, JAK3 and tyrosine kinase 2(TYK2). These intracellular proteins are characterized by an amino-terminal portion of approximately 600 amino acids and two kinase domains, each of about 250 residues, separated by a short hinge region. While the expression of JAK1, JAK2 and TYK2 is ubiquitous, JAK3 is expressed predominantly in hematopoetic cells. JAKs are activated upon high-affinity binding of a variety of cytokines to their multimeric cell-surface receptors. When activated, JAKs can phosphorylate the cytokine receptors, creating docking sites for signaling molecules, especially members of the STAT family.IFN-α/β binds to a heterodimeric receptor complex that consists of IFNAR1 and IFNAR2. JAK1 is associated with IFNAR2 while TYK2 is associated with IFNAR1. Besides a signal transduction function, TYK2 is also essential for stable cell surface expression of IFNAR1. This is because TYK2 slows down IFNAR1 degradation, at least in part due to inhibition of IFNAR1 endocytosis. Following IFN-α/β binding, the JAK kinases are activated and tyrosine phosphorylated. This leads to the phosphorylation of STATs 1,2 and 3. Phosphorylated STAT1 and STAT2 heterodimerize and translocate to the nucleus. Marburg virus(MARV) is a filovirus that is known to counteract innate antiviral responses of the host, particularly the IFN-α/β response, to promote uncontrolled virus replication in vivo. Studies have shown that the mode of action of MARV involves its matrix protein VP40 that inhibits JAK1 and TYK2 function thus inhibiting IFN-α/β signaling.

IFN-γ binds to and activates its receptor which is composed of the IFNγRα and IFNγRB subunits. JAK1 is associated with the former and JAK2 is associated with the latter subunit. Upon ligand binding, the JAKs are phosphorylated as well as IFNγR. This leads to the phosphorylation of STAT1 which homodimerizes and translocates to the nucleus. As is the case with IFN-α/β, IFN-γ signaling is inhibited by the MARV matrix protein VP40 which targets both JAK1 and JAK2. Other inhibitors of IFN-γ signaling include SOCS-1 and TC-PTP.


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