Role of JAK1 and JAK3 in γc Cytokine Signaling

Janus kinases (JAK) are a family of intracellular protein tyrosine kinases of 120-140 kDa. They 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. 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 and is highly regulated with cell development and activation. JAKs are activated upon high-affinity binding of a variety of cytokines to their multimeric cell-surface receptors. Between one and three JAK members can be activated depending on the ligand.The JAK3 kinase along with JAK1 are involved in signal transduction of the γchain (γc) family of cytokines which consists of IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. The cytokines are so named because their receptors share a common γc subunit besides having a cytokine specific α/B subunit. γc family cytokines signal through the JAK-STAT pathway. JAK3 exclusively binds the γc subunit while JAK1 binds the α/B subunit. IL-2 is the prototypic member of this family. IL-2R consists of three chains (IL-2Rα, IL-2Rβ and γc), which together form the high affinity IL-2R. Upon ligand binding, JAK1 and JAK3 are phosphorylated. They in turn activate and phosphorylate transcription regulators STAT5a and STAT5b. The STATs then heterodimerize and translocate to the nucleus where they regulate gene expression. JAK1 also activates the ERK and PI3K signaling pathways. Several factors are responsible for attenuating the signals initiated by IL-2 binding to and activating its receptor. These include SOCS1 (JAK1/JAK3 inhibitor), SOCS3 (JAK1 inhibitor) and a tyrosine phosphatase SHP-2 (JAK3 inhibitor). IL-15R shares the IL-2Rβ and γc subunits but has a specific IL-15Rα subunit. In the case of IL-15, activation on JAK1 and JAK3 leads to phosphorylation and activation of STAT3/5.Other members of the γc family of cytokines such as IL-4, IL-7, IL-9, IL-21 possess a ligand specific α-subunit besides the shared γc subunit. Ligand binding to the receptor results in the activation and phosphorylation of JAK1 and JAK3 which in turn activate STATs 1/3/5. IL-4R is also able to activate STAT6. Phosphorylated STATs homo- or hetero-dimerize and translocate to the nucleus where they regulate gene expression. The SOCS family is one of the important negative regulators of signaling mainly by inhibiting JAK1 or JAK3. TSLP is a related cytokine. It binds to a receptor that has a specific TSLPR subunit while sharing a common IL-7Rα subunit. Lacking the γc subunit, TSLP signals via JAK1 and JAK2 rather than JAK3.