What does the JAK2 gene do? What is the function of the JAK2 kinase?
The JAK2 is an abbreviation for Janus kinase A2 (Janus-the Roman god of gates and passages; Just another kinase was the first and original name for this gene). The JAK2 gene was discovered by Wilks et al. in 1989 while they investigated the processes related to cytokine and growth factor signaling [citation].
The JAK2 gene is located on the short arm of chromosome 9, roughly 145,559 MB long. The JAK2 gene encodes the Janus kinase 2 kinase belonging to a non-receptor tyrosine kinases group. The JAK2 kinase is involved in cell signaling processes, promoting cellular growth and controlling red blood cell numbers, white blood cells, and platelets.
The JAK2 kinase is an essential element in cytokine receptor signaling, which is further vital in processes for ligand binding and phosphorylation of signal transducers and transcription factors (STAT) [citation]. Important to mention that the JAK2 kinase is one of the critical elements in the JAK/STAT pathway. The JAK/STAT pathway is involved in already mentioned cytokine receptor signaling processing signals that are further important for cellular division, cell growth, immunity, and other processes. Figure 1 illustrates the JAK-STAT signaling pathway.
Figure 1: Illustration of JAK-STAT signaling pathway (source: KEGG PATHWAY Database)
What other Janus kinases are there?
Besides the JAK2 kinase, there are other Janus kinases, such as Janus kinases 1, 2, and 3 and tyrosine kinase 2, and all these are members of so-called the Janus kinase family [citation].
The JAK2 kinase promotes the growth and division of cells. It is a member of the JAK-STAT signaling pathway. It also controls the production of blood cells from hematopoietic cells [citation].
The JAK2 kinases’ central role is in the transducing the signal from different growth factor receptors such as:
Erythropoietin (EPO)
Granulocyte-macrophage colony-stimulating factor
Interleukin-3
Stem cell factor
Insulin-like growth factors 1, and
Thrombopoietin [citation].
The JAK2 FERM domain is involved in the trafficking of erythropoietin (EPO) receptors to the cell surface. After the binding of EPO, a conformational change occurs, leading to the activation or recruitment of signal transducers and activators of transcription molecules (STAT). STAT molecules are then phosphorylated and passed to the nucleus, where they have a role as transcriptional factors. This event also has a vital role in other cytokine signaling pathways [citation].
What are the biological processes in which the JAK2 gene product is involved?
The JAK2 kinase controls the growth and differentiation of platelets and erythrocytes by regulating thrombopoietin (TPO) and erythropoietin (EPO) receptor signaling [citation].
The JAK2 kinase is activated by transphosphorylation by a receptor, and then it phosphorylates multiple sites on cytokine receptors, further leading to the formation of docking sites for the SH2 domain. Those sites contain signal transducers and activators of transcription (STATs), some proteins, and protein phosphatase. STATs are further transported to the nucleus to initiate transcription [citation].
What are tyrosine kinases, and what are their functions?
Tyrosine kinases are important mediators of the signaling cascade, involved in diverse biological processes like cellular growth, differentiation, metabolism, and apoptosis in response to external and internal stimuli [citation]. Phosphorylation of tyrosine residues modulates enzymatic activity and creates binding sites to recruit downstream signaling proteins. If you want to learn more about kinases and understand phosphorylation, please check the following blog posts on kinases and phosphorylation. Two classes of PTKs are present in cells: the transmembrane receptor PTKs and the non-receptor PTKs [citation].
Why are tyrosine kinases essential?
Tyrosine kinases are essential for many biological processes, such as cell growth, differentiation, metabolism, and apoptosis. In addition, their function is essential in normal cells, and mutations in genes encoding tyrosine kinases may transform and interfere with their activity [citation].
What are non-receptor tyrosine kinases?
Non-receptor tyrosine kinases (NRTK) are cytoplasmic proteins characteristic of their important structural variability. NRTK contains a kinase domain and often possesses several additional signaling or protein-protein interacting domains, such as SH2, SH3, and PH domains [citation].
What is the difference between non-receptor tyrosine kinases and receptor tyrosine kinases?
Tyrosine kinases are primarily classified as:
Receptor tyrosine kinase (RTK), for example, EGFR, PDGFR, FGFR, and IR, and
Non-receptor tyrosine kinase (NRTK): SRC, ABL, FAK, and Janus kinase.
RTKs are transmembrane glycoproteins that are activated by the binding of their ligands. RTKs convert a signal from outside the cell to a signal inside the cell (cytoplasm) by modifying (autophosphorylation) tyrosine residues and downstream signaling proteins [citation].
Unlike other activation mechanisms, the activation mechanism of NRTK is more complex and involves different proteins interacting with each other to enable transphosphorylation [citation].
Moreover, all non-receptor tyrosine kinases have two similar ‘active’ and ‘inactive’ domains, and this is the reason why some of them got the name Janus. Janus was a Roman god who could look simultaneously in two directions [citation].
What is the Janus kinase family of tyrosine kinases? What is the structure of JAK kinases? What is their role?
Janus tyrosine kinases are non-receptor tyrosine kinases and are a unique family of tyrosine kinases. Different JAKs and STATs are recruited based on their tissue specificity and the receptors engaged in the signaling event [citation].
The JAK family consists of four members:
Janus kinase 1 (JAK1)
Janus kinase 2 (JAK2)
Janus kinase 3 (JAK3), and
non-receptor tyrosine-protein kinase (TYK2) which have different association patterns with receptors.
JAK1 and JAK2 are essential during development [citation].
Each JAK has [citation]
The kinase domain: The kinase domain is the JAK homology 1 (JH1) domain, and it is the central region of JAK2. It possesses the catalytic activity that phosphorylates tyrosine residues on the receptors and STAT proteins.
The pseudokinase domain: The pseudokinase domain is a catalytically inactive pseudokinase domain, JAK homology 2 (JH2). This domain is located at the C-terminus of JAK2 and has structural similarity to the kinase domain but lacks catalytic activity. It is believed to play a regulatory role in JAK2 activity and localization.
The SH2 domain: This is the SRC homology 2 (SH2) domain located near the C-terminus of JAK2. The SH2 domain is responsible for binding to phosphorylated tyrosine residues on the receptors and STAT proteins, allowing JAK2 to phosphorylate them and initiate downstream signaling.
The FERM domain. This is the amino-terminal domain located at the N-terminus of JAK2. This is the domain where JAK2 binds to cytokine type 1 receptor which further initiates JAK2 activation.
Figure 2: Lolliplot diagram of JAK2 protein structure and mapped somatic mutations. Diagram built using cBioPortal
Why are Janus kinases important?
As already mentioned, Janus kinases interact with dozens of cytokines and growth factors. Outputs of those interactions result in cell proliferation, cell differentiation, cell migration, apoptosis, or cell survival.
Also, Janus kinases are activators of the JAK-STAT signaling pathway important for homeostasis, hematopoiesis, immune cell development, stem cell maintenance, etc. [citation]. JAKs are important as therapeutic targets because they are associated with immune system disorders and hematopoietic events [citation].