Sandbox Reserved 598: Difference between revisions
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== | == Background == | ||
[[Image:MyJak2.jpg|thumb|250px|left|Not, "just another kinase"]] | [[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]] | 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]] | ||
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The structure of Jak 2 can be broken down into seven separate components, as seen in the pictured diagram to the left. The top, gray, portion of the protein was found to be the N-terminal lobe (residues 840-931). This loop is comprised of a 5-stranded anti-parallel beta-sheet (Beta1 - 5) and one alpha-helix (alpha C). The large dark green portion seen on the bottom is the COOH-terminal lobe. This carboxylic acid lobe is comprised of 8 alpha-helices (alpha D-alpha K), and 3 3/10 helices (3/10B, 3/10C, 3/10D), and 3 pairs of anti-parallel Beta-strands (Beta7-8, 6-9, and 10-11). The orange portion in the middle-right of the protein is the glycine loop which makes contacts with the activation loop and catalytic loop. This glycine loop, while small, is of great importance, as it is known to be essential in substrate and nucleotide binding. In yellow, to the top-left, there is a hinge region present which aids in molecule interactions. The blue section in the low middle is the catalytic loop, the red loop to the right is the activation loop and finally the dark blue section towards the bottom-right is the JAK2 lip which contains one 3/10C helix and one alpha-helix connected by a short linker. <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> | The structure of Jak 2 can be broken down into seven separate components, as seen in the pictured diagram to the left. The top, gray, portion of the protein was found to be the N-terminal lobe (residues 840-931). This loop is comprised of a 5-stranded anti-parallel beta-sheet (Beta1 - 5) and one alpha-helix (alpha C). The large dark green portion seen on the bottom is the COOH-terminal lobe. This carboxylic acid lobe is comprised of 8 alpha-helices (alpha D-alpha K), and 3 3/10 helices (3/10B, 3/10C, 3/10D), and 3 pairs of anti-parallel Beta-strands (Beta7-8, 6-9, and 10-11). The orange portion in the middle-right of the protein is the glycine loop which makes contacts with the activation loop and catalytic loop. This glycine loop, while small, is of great importance, as it is known to be essential in substrate and nucleotide binding. In yellow, to the top-left, there is a hinge region present which aids in molecule interactions. The blue section in the low middle is the catalytic loop, the red loop to the right is the activation loop and finally the dark blue section towards the bottom-right is the JAK2 lip which contains one 3/10C helix and one alpha-helix connected by a short linker. <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> | ||
== | == Function == | ||
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> | 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> | ||
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== Conditions Associated with Jak2 Mutations == | == Conditions Associated with Jak2 Mutations == | ||
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> | 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> | ||
== Current and Future Therapies == | |||
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> | |||
