Jak Kinases

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Jak Kinases Background

About Jak Kinases

Janus kinases (JAK) are a family of intracellular non-receptor tyrosine kinases ranging in size from 120-140 kDa that transduce cytokine-mediated signals via the JAK-STAT pathway. They were initially named "just another kinase" 1 and 2 (since they were just two of many discoveries in a PCR-based screen of kinases), but were ultimately published as "Janus kinase". The name is taken from the two-faced Roman god of beginnings, endings, and duality, Janus, because the JAKs possess two near-identical phosphate-transferring domains. One domain exhibits the kinase activity, while the other negatively regulates the kinase activity of the first.

The Janus kinase (Jak) family, which includes Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and Tyrosine kinase 2 (TYK2), binds cytokine receptors through the amino-terminal FERM structural domain and connects them to other molecules, especially members of the signal transducer and activator of transcription (Stat) family. Transgenic mice that do not express JAK1 have defective responses to some cytokines, such as interferon-gamma. JAK1 and JAK2 are involved in type II interferon (interferon-gamma) signaling, whereas JAK1 and TYK2 are involved in type I interferon signaling. Mice that do not express TYK2 have defective natural killer cell function.

A schematic representation of the primary structure of Janus kinases (Jaks). Fig.1 A schematic representation of the primary structure of Janus kinases (Jaks). (Yamaoka K, et al., 2004)

Mechanism and Functions of Jak Kinases

Since members of the type I and type II cytokine receptor families possess no catalytic kinase activity, they rely on the JAK family of tyrosine kinases to phosphorylate and activate downstream proteins involved in their signal transduction pathways. The receptors exist as paired polypeptides thus exhibiting two intracellular signal-transducing domains. JAKs are associated with a proline-rich region in each intracellular domain, which is adjacent to the cell membrane and called a box1/box2 region. After the receptor associates with its respective cytokine/ligand, it goes through a conformational change, bringing the two JAKs close enough to phosphorylate each other. The JAK autophosphorylation induces a conformational change within itself enabling it to transduce the intracellular signal by further phosphorylating and activating transcription factors called STATs. The activated STATs dissociate from the receptor and form dimers before translocating to the cell nucleus where they regulate transcription of selected genes.

Some examples of molecules that use the JAK/STAT signaling pathway include colony-stimulating factors, prolactin, growth hormone, and many cytokines. Janus kinase has also been reported to play a role in maintaining X chromosome inactivation.

An overview of cytokine signaling.Fig.2 An overview of cytokine signaling. (Yamaoka K, et al., 2004)

Applications of Jak Kinases

Janus kinases (Jak) play a key role in cytokine and growth factor signaling. These kinases are involved in a variety of cellular processes including cell growth, differentiation, immune response, and hematopoiesis. There are many other key roles, such as:

  • Signal Transduction Studies

Jak kinases are important components of signaling pathways initiated by cytokines and growth factors. By phosphorylating specific tyrosine residues, Jak kinase activates downstream signal transducer and activator of transcription (STAT) proteins to regulate gene expression. Understanding the precise mechanisms and signaling cascades mediated by Jak kinase is essential for elucidating cellular responses to various stimuli and developing targeted therapeutic interventions.

  • Drug Discovery and Development

Dysregulated Jak kinase signaling has been implicated in a variety of diseases, including cancer, autoimmune diseases, and inflammatory disorders. Targeting Jak kinase has emerged as a promising therapeutic strategy. JAK inhibitors are used to treat atopic dermatitis and rheumatoid arthritis. They are also used in the treatment of psoriasis, true erythrocytosis, alopecia areata, primary thrombocythemia, ulcerative colitis, myelofibrosis with myelofibrosis, and vitiligo. Examples include tofacitinib, baricitinib, upatinib, and fingolitinib (GLPG0634).

  • Biomarker Identification

Activation of Jak kinase and its downstream signaling pathways can serve as diagnostic and prognostic markers for a variety of diseases. Monitoring the activity of Jak kinase or downstream STAT proteins in patient samples can help in disease diagnosis, treatment stratification, and monitoring response to therapy.

Research Tools for Jak Kinases

Jak kinase plays a critical role in cell signaling and is an attractive target for therapeutic intervention. Creative BioMart offers a wide range of products and services to support Jak kinase research, including tools for signal transduction studies, drug discovery and development, and biomarker identification. By utilizing these resources, researchers can deepen our understanding of the Jak kinase pathway. Click to view all related molecules/targets and research reagents. Please get in touch with us with any questions or requests.

Reference:

  1. Yamaoka K, Saharinen P, Pesu M, et al. The janus kinases (jaks)[J]. Genome biology, 2004, 5(12): 1-6.
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