JAK2

What is JAK2 Protein?

JAK2 gene (Janus kinase 2) is a protein coding gene which situated on the short arm of chromosome 9 at locus 9p24. This gene encodes a non-receptor tyrosine kinase that plays a central role in cytokine and growth factor signalling. The primary isoform of this protein has an N-terminal FERM domain that is required for erythropoietin receptor association, an SH2 domain that binds STAT transcription factors, a pseudokinase domain and a C-terminal tyrosine kinase domain. Cytokine binding induces autophosphorylation and activation of this kinase. This kinase then recruits and phosphorylates signal transducer and activator of transcription (STAT) proteins. Growth factors like TGF-beta 1 also induce phosphorylation and activation of this kinase and translocation of downstream STAT proteins to the nucleus where they influence gene transcription. The JAK2 protein is consisted of 1132 amino acids and JAK2 molecular weight is approximately 130.7 kDa.

What is the Function of JAK2 Protein?

JAK2 is involved in the transduction of various cytokine and growth factor signals. When a cytokine binds to its receptor, JAK2 is activated, which in turn activates downstream signaling pathways, such as the JAK-STAT pathway. JAK2 promotes cell proliferation, differentiation and survival by activating transcription factors such as STAT proteins. JAK2 plays an important role in the development and function of immune cells, influencing the regulation of immune responses. JAK2 is also involved in cellular responses to stress, including responses to hypoxia, nutrient deficiency, and cytokine deprivation. JAK2 is involved in the regulation of gene expression by influencing the phosphorylation of transcription factors.

Fig1. Schematic of JAK2 activation. (Olli Silvennoinen, 2015)

JAK2 Related Signaling Pathway

The main function of JAK2 is to participate in the JAK-STAT signaling pathway. When a cytokine or growth factor binds to its receptor, JAK2 is activated and phosphorylates the STAT protein, which diomerizes and moves into the nucleus, regulating the expression of specific genes. JAK2 is involved in the transduction of various cytokine signals, such as interferon and growth factors, which affect cell proliferation, differentiation and survival. JAK2 plays a key role in the development and function of immune cells, especially T cells and natural killer (NK) cells, and is involved in the regulation of immune responses. JAK2 is involved in cellular responses to a variety of stresses, including responses to hypoxia, nutrient deficiency, and cytokine deprivation. JAK2 is also involved in the regulation of apoptosis, and the abnormal activity of JAK2 may lead to the imbalance of apoptosis.

JAK2 Related Diseases

GOF mutations in the JAK2 gene are a molecular feature of a variety of myeloproliferative tumors, such as polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF), which are characterized by excessive proliferation of blood cells. Loss of JAK3 is associated with severe combined immunodeficiency (SCID), and certain mutations in JAK1 are also associated with immunodeficiency. Certain variants of the JAK2 gene have been linked to autoimmune diseases such as rheumatoid arthritis (RA), for which JAK inhibitors have been used. The function of JAK2 protein is also associated with a number of other diseases, such as systemic lupus erythematosus (SLE) and Sjogren's syndrome.

Bioapplications of JAK2

With a better understanding of JAK2 activation mechanisms, the development of JAK inhibitors has opened up new avenues, including multi-target drugs and local therapies, as well as targeted protein degradation strategies. JAK2 is a popular target for drug development, and several JAK inhibitors have been approved for the treatment of different diseases, while several other inhibitors are in clinical trials. JAK2 inhibitors such as Ruxolitinib Phosphate are approved in 18 countries for the treatment of a variety of diseases, including polycythemia vera and primary myelofibrosis. JAK2 inhibitors are also used in the treatment of rheumatoid arthritis (RA), psoriasis and other autoimmune diseases, of which Tofacitinib is the first JAK inhibitor approved for the treatment of RA and inflammatory bowel disease (IBD).