JAK

Janus kinases (or JAKs) are a family of nonreceptor tyrosine kinases that function downstream of cytokine receptors. Following activation of a cytokine receptor JAKs phosphorylate the transcription factors known as STATs and initiate the JAK-STAT signaling pathway. Four JAK family members have been identified (JAK1, JAK2, JAK3 and Tyk2), which share a similar protein domain structure: a kinase domain (JH1), a 'pseudo'-kinase domain that regulates the kinase activity of JH1, a SH2 domain and an NH₂-terminal domain known as the FERM domain.

The FERM domain of Janus kinase family members mediates the association of JAK with other enzymes and cytokine receptors. The JAK Tyk2 associates with the IFN-1, IL-6, 10, 12, and 23 cytokine receptor families. JAK1 mediates signals from IFN-α,β,γ and IL-2, 6 receptors. JAK2 transduces signals from the single chain and IL-3 cytokine receptor families, and from the IFN-γ receptors. JAK3 associates with the IL-2 receptor γ-chain.

Janus Kinases and Inflammation

JAK/STAT signaling mediates the effects of a wide range of inflammatory cytokines. JAK inhibitors have been approved for the treatment of inflammatory and autoimmune diseases, including baricitinib (Cat. No. 7222) for rheumatoid arthritis and ruxolitinib (Cat. No. 7064) for graft-versus-host disease.

The JAK/STAT pathway is implicated in the cytokine storm (also known as cytokine release syndrome) associated with severe infection, particularly COVID-19. IL-6, an important mediator of cytokine storm, activates JAK/STAT signaling via two separate mechanisms termed cis and trans signaling pathways. The cis signaling pathway, involves the activation of JAK and STAT3 via membrane-bound IL-6 receptors (mIL-6R) and gp130 receptors and has multiple effects on the innate and adaptive immune systems, while the trans signaling pathway activates JAK/STAT3 signaling in cells that express gp130 but not mIL-6R, such as endothelial cells. These actions result in increased cytokine production and contribute to the poor clinical outcomes associated with COVID-19. Baricitinib and ruxolitinib have both been investigated for their potential to reduce the cytokine storm in COVID-19 patients.

The Role of Janus Kinases in Cytokine Storm

Figure 1: Schematic highlighting the role of the JAK/STAT-Signaling pathway in the perpetuation of cytokine storm. Activated immune cells release cytokines including interleukin-6, which activates JAK/STAT signaling via two separate pathways, known as trans- and cis-signaling, leading to further cytokine release. Adapted from More & June (2020) Cytokine release syndrome in severe COVID-19. Science 368 473.

Janus Kinases and Cancer

In addition to its role in inflammation, the IL-6/JAK/STAT signaling axis is also associated with certain cancers, particularly myeloproliferative neoplasms (MPN). Abnormal hyperactivation of the pathway drives tumor proliferation, invasiveness and metastasis, as well as immune evasion.

JAK2 also has a role as an Epigenetic Writer, that is an enzyme that catalyzes the addition of chemical groups to histone tails, as it is involved in the phosphorylation of histone proteins. This key epigenetic modification results in changes in chromatin architecture and therefore gene expression.

External sources of pharmacological information for JAK :

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Pathways for JAK

JAK-STAT Signaling Pathway

The JAK-STAT signaling pathway has several roles, including the control of cell proliferation and hematopoiesis. It is the main signal transduction cascade from cytokine receptors.

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JAK Gene Data