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[[Image:MyJak2.jpg|thumb|250px|left|Not, "just another kinase"]]

Janus Kinase 2 is a non-receptor janus kinase, a protein which is part of the tyrosine kinases. These group of kinases are the primary intracellular mediators of cytokine signaling and are involved in the control of cellular growth. As a non-receptor kinase, Jak 2 has a cytoplasmic enzyme which catalyzes the transfer of a phosphate group through phosphorylation to the tyrosine residue in the protein.  Such an enzyme plays a crucial role in regulating various cellular functions by switching on or off additional enzymes within the cell. <ref> Hanks, SK., Quinn, AM., Hunter, T. (1988). The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science 241 (4861): 42–52. doi:10.1126/science.3291115. PMID 3291115. </ref> Such phosphorylation is a reversible process, and used in many different pathways as a method to control cellular activity. However kinases like Jak2, have enzymes which add phosphate groups to hydroxyl side chains as can be seen in the diagram. <ref> Hudel, H. “Center for Biomembrane Systems at UC Irvine” http://bass.bio.uci.edu </ref> [[Image:Phosphorylation.png]]

Jak2 was given its name "Janus" after the two-faced Roman God "Janus" who was known as the custodian of the universe and the God of new beginnings. <ref> Kirwan, J. (02, 2011 03). Janus incarnate. Retrieved from http://rense.com/general92/janus.htm http://rense.com/general92/janus.htm </ref> The abbreviation 'Jak' is commonly referred to as 'just another kinase' as, when it was first discovered, the kinase's role was not yet fully understood. <ref> Weinberg, I. (April 2010). Janus Kinase (Jak2)”. Vascular Medicind; Angiolgist http://www.angiologist.com/general-medicine/janus-kinase-2-jak2/ </ref>

In determining the three-dimensional structure of the Jak2 protein, three primary methods of analysis were used; protein expression and purification, crystallization, and x-ray data collection. <ref> Lucet, I., Fantino, E., & Styles, M. (2005). The structural basis of janus kinase 2 inhibition by a potent and specific pan-janus kinase inhibitor. Blood, 107, 176-183. doi: 10.1182/blood-2005-06-2413 http://bloodjournal.hematologylibrary.org/content/107/1/176.full.pdf </ref> In the protein expression and purification the Jak2 residue was cloned using pFastBac which uses “two promoters in a single vector for expression of two proteins simultaneously in insect cells”. <ref> http://www.invitrogen.com/1/1/14896-pfastbac-dual.html </ref> The bacmid DNA with the kinase insert was then isolated and put into cells of insect army worms. The cells were then grown, lysed and centrifuged after which the protein was then incubated, separated with gel filtration and fractions were taken for crystallization trials. In these crystallization trials, the protein residue was used to grow crystals via hanging drop vapor-diffusion. The purified protein complex was then mixed with solutions which subsequently formed crystals after one to three days. The crystalized protein was then flash frozen and the structure  determined via molecular replacement and the AmoRe program. <ref> ) Lucet, I., Fantino, E., & Styles, M. (2005). The structural basis of janus kinase 2 inhibition by a potent and specific pan-janus kinase inhibitor. Blood, 107, 176-183. doi: 10.1182/blood-2005-06-2413 http://bloodjournal.hematologylibrary.org/content/107/1/176.full.pdf </ref>

In the unbound and inactive state of Jak2, the FERM (JH4-7), JH1 (kinase domain) and JH2 (pseduokinase domain) domains of are tightly folded together preventing the catalytic domain from being active. (Figure 1)  However, the first activation step of  Jak2 is the displacement of the FERM domain by its interaction with the receptor which begins the unfolding of domains within the protein to allow access to the various binding domains. (Figure 2). In the presence of a ligand, receptor aggregation occurs. As a result of this aggregation, the tyrosine within the Jak2 active loop is phosphorylated and then induces changes in both JH2 and JH1 domains. Once phosphorylation occurs within the activation loop, the kinase is fully activated. (Figure 3) Under normal conditions, Jak2 is not associated with a receptor and is locked into an inactive state. Receptor binding through the FERM domain relieves steric constraints, and allows Jak2 to be activated once it is engaged with its erythropoietin receptor. Activation of Jak2 by erythropoietin receptor engagement leads to the tyrosine phosphorylation of the receptor and Jak2. <ref> Funakoshi-Tago, M., Pelletier, S., & Moritake, H. (2008). Jak2 ferm domain interaction with the erythropoietin receptor regulates jak2 kinase activity. Molecular and Cellular Biology, 28(5), 1792-1801. doi: 10.1128/MCB.01447-07  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2258779/ </ref>

[[Image:Jak2Mutation.png|thumb|250px|left|Figure 4]]

[[Image:Jak2DNA.png|thumb|250px|left|Figure 5]] Figure 5 shows the amino acid sequence alignment of JAK2 along with the other members of the JAK family TYK2, JAK3, and JAK1 and the kinase domain of FAK and LCK around the Lip region. Cylinders show alpha-helices, the residues  conserved among the JAK kinases sequence are highlighted in red. The dark gray boxes indicate which residues are conserved to at least 75% within the janus kinase family and finally the light gray boxes indicate conservatively substituted residues. <ref> ) Lucet, I., Fantino, E., & Styles, M. (2005). The structural basis of janus kinase 2 inhibition by a potent and specific pan-janus kinase inhibitor. Blood, 107, 176-183. doi: 10.1182/blood-2005-06-2413 http://bloodjournal.hematologylibrary.org/content/107/1/176.full.pdf </ref>

As Janus Kinase 2 has a significant role in hematopoiesis, the formation and development of blood cells, mutations in the protein most commonly result in constitutive kinase activation which lead to oncogenesis. Some of the cancers associated with such mutations have been found to be myeloid leukemia, lymphoid leukemia, polycythemia vera, along with other myeloproliferative neoplasms. <ref> Funakoshi-Tago, M., Pelletier, S., & Moritake, H. (2008). Jak2 ferm domain interaction with the erythropoietin receptor regulates jak2 kinase activity. Molecular and Cellular Biology, 28(5), 1792-1801. doi: 10.1128/MCB.01447-07  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2258779/ </ref> While there are many different genetic mutations which are resultant of leukemias, 85% of patients diagnosed with polycythemia vera are found to have the mutation in their Jak2 protein. <ref> http://www.mayoclinic.com/health/polycythemia-vera/DS00919 </ref>  

There are currently many therapies for differing forms of leukemia, some of which include cytoreductive medications such as hydroxyurea or agrylin, to suppress the bone marrow’s ability to make blood cells, cell destructive medications like cytoxin which act as oral chemotheraputic agents, interferon treatments to stimulate the patient's immune response to fight and kill overproduction or white and red blood cells. Finally traditional chemotherapy is commonly used, as well, for both leukemias as well as progressive polycythemia vera. <ref> http://m.cancer.gov/topics/treatment/bycancer/adultAML/Patient </ref> <ref> http://www.mayoclinic.com/health/chronic-lymphocytic-leukemia/DS00565 </ref> <ref> http://www.mayoclinic.com/health/polycythemia-vera/DS00919 </ref> <ref> Medscape Reference (01, 2012, 10) Polycythemia Treatment and Management. Retrieved from: http://emedicine.medscape.com/article/205114-treatment </ref> While there are a few Jak2 inhibitors already in use which use competitive inhibition for ATP binding pockets, they are not extremely effective due to non-specificity. Due to this issue with specificity, the current therapies for Jak2 mutations are being more focused on allosteric inhibition designs. This research is believed to be hopeful due to the successes it has had with other, different, kinase inhibition. Possible sites which scientists are targeting for such inhibition include, the type II Inhibitor pocket, substrate binding sites, kinase pseudo kinase domain interface, SH2JK2 Linker Region, and the FERM Domain. Currently many of these are in both pre and post clinical trials. <ref> Gnanasambandan, K., & Sayeski, P. (2011). A structure-function perspective of jak2 mutations and implications for alternate drug design strategies: the road not taken. Department of Physiology and Functional Genomics, University of Florida College of Medicine, 18(30), 59-73. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/21864276 http://www.ncbi.nlm.nih.gov/pubmed/21864276 </ref>