Sandbox Reserved 598: Difference between revisions

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==The Function of Jak2 ==

There are four members of the janus kinase family, Jak1, Jak2, Jak3, and Jak4. Each kinase has unique functions based on their respective abilities to bind to different cytokine receptors. Out of those four janus kinases, Jak2 is responsible for erythropoietin and thrombopoietin signaling which then causes the proliferation, activation and transcription of blood cells. <ref> Weinberg, I. (April 2010). Janus Kinase (Jak2)”. Vascular Medicind; Angiolgist http://www.angiologist.com/general-medicine/janus-kinase-2-jak2/</ref> The Jak2 Signal Transducers and Activators of Transcription (STAT) pathway is what influences the kinase ability. The janus kinase-STAT pathway is the central path taken for such cell signal transcription though the erythropoietin receptor. <ref> O'Shea, J., Gadina, M., & Chen, X. (2005). Structure of a janus kinase: molecular insights and prospects for optimizing a new class of immunosuppressants. The Journal of the American Society of Hematology, 106(3), 765-766. doi: 10.1182/blood-2005-05-1947 http://bloodjournal.hematologylibrary.org/content/106/3/765.full </ref> Under normal conditions, various levels of regulation maintain Jak2 in its inactive form until receptor activation occurs and involve interactions of the pseudokinase domain (JH2) and FERM domain (JH4 to -7) with the kinase domain (JH1). <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>

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>

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 ==The Function of Jak2 ==
 There are four members of the janus kinase family, Jak1, Jak2, Jak3, and Jak4. Each kinase has unique functions based on their respective abilities to bind to different cytokine receptors. Out of those four janus kinases, Jak2 is responsible for erythropoietin and thrombopoietin signaling which then causes the proliferation, activation and  transcription of blood cells. <ref> Weinberg, I. (April 2010). Janus Kinase (Jak2)”. Vascular Medicind; Angiolgist http://www.angiologist.com/general-medicine/janus-kinase-2-jak2/</ref> The Jak2 Signal Transducers and Activators of Transcription (STAT) pathway is what influences the kinase ability. The janus kinase-STAT pathway is the central path taken for such cell signal transcription though the erythropoietin receptor. <ref> O'Shea, J., Gadina, M., & Chen, X. (2005). Structure of a janus kinase: molecular insights and prospects for optimizing a new class of immunosuppressants. The Journal of the American Society of Hematology, 106(3), 765-766. doi: 10.1182/blood-2005-05-1947 http://bloodjournal.hematologylibrary.org/content/106/3/765.full </ref> Under normal conditions, various levels of regulation maintain Jak2 in its inactive form until receptor activation occurs and involve interactions of the pseudokinase domain (JH2) and FERM domain (JH4 to -7) with the kinase domain (JH1). <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>
+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>