# JAK2

## Overview
JAK2 (Janus kinase 2) is a gene that encodes a non-receptor tyrosine kinase, which plays a pivotal role in the JAK-STAT signaling pathway. This pathway is crucial for mediating the effects of cytokines and growth factors on cellular processes such as proliferation, differentiation, and apoptosis (Perner2019Roles; Ihle2007Jak2:). The protein product of JAK2, Janus kinase 2, is characterized by its complex structure, including functional domains such as the FERM, SH2-like, and kinase domains, which facilitate its interactions with cytokine receptors and other signaling molecules (Sandberg2004Jak2; Giordanetto2002Prediction). JAK2 is integral to hematopoiesis and immune function, and its dysregulation, often through mutations like JAK2V617F, is implicated in various myeloproliferative neoplasms and other hematological disorders (Morgan2008A; Tefferi2010Novel). Understanding the structure and function of JAK2 is essential for developing targeted therapies for these conditions (Lee2013The; Gäbler2013JAK2).

## Structure
JAK2 (Janus kinase 2) is a non-receptor tyrosine kinase with a complex molecular structure comprising several functional domains. The primary structure of JAK2 includes a sequence of amino acids forming distinct domains such as the FERM domain, SH2-like domain, and kinase domains (JH1 and JH2) (Sandberg2004Jak2; Giordanetto2002Prediction). The FERM domain, spanning JH7 to the middle of JH4, is involved in interactions with cytokine receptors and contains a hydrophobic pocket crucial for binding (Giordanetto2002Prediction). The JH1 domain is a typical tyrosine kinase domain with two lobes: an N-terminal lobe with a twisted β-sheet and an α-helix, and a mainly α-helical C-terminal lobe (Lindauer2001Prediction).

The secondary structure of JAK2 includes alpha helices and beta sheets, contributing to the stability and function of its domains (Lindauer2001Prediction). The tertiary structure involves the folding of these domains, with the JH1 and JH2 domains forming a complex that regulates kinase activity through hydrophobic and electrostatic interactions (Wan2013Ab). The quaternary structure of JAK2 involves dimerization, which is essential for its activation and function (Wan2013Ab).

Post-translational modifications, particularly phosphorylation, play a significant role in JAK2's function. Key phosphorylation sites include Y1007 and Y1008, which are critical for its activation (Hall2010Expression). JAK2 also has splice variant isoforms that can influence its activity and interactions (Sandberg2004Jak2).

## Function
The JAK2 gene encodes a non-receptor tyrosine kinase that plays a crucial role in the JAK-STAT signaling pathway, which is essential for transmitting signals from cytokine receptors to the cell nucleus, influencing gene expression and regulating various cellular processes. In healthy human cells, JAK2 is involved in hematopoiesis, immune function, and cell growth (Perner2019Roles; Ihle2007Jak2:). It is activated by cytokines and growth factors, and its kinase activity is regulated through interactions with specific domains in receptors and phosphorylation within the activation loop (Ihle2007Jak2:).

JAK2 localizes to the plasma membrane, cytoplasm, endoplasmic reticulum, and centrosomes, where it participates in microtubule organization and cell cycle regulation (Shahi2022The). The SH2 domain and kinase activity of JAK2 are essential for its localization to the centrosome, which is important for regulating cell growth and centrosome amplification (Shahi2022The). JAK2 also influences the activation of Signal Transducers and Activators of Transcription (STATs), particularly STAT5, which regulates gene transcription and is crucial for cell proliferation and differentiation (Perner2019Roles; Shahi2022The). Through these mechanisms, JAK2 maintains normal cellular signaling and function, contributing to organismal outcomes such as proper blood cell development and immune responses (Perner2019Roles; Ihle2007Jak2:).

## Clinical Significance
Mutations in the JAK2 gene, particularly the JAK2V617F mutation, are significantly associated with myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) (Morgan2008A; Tefferi2010Novel). The JAK2V617F mutation leads to constitutive activation of the JAK-STAT signaling pathway, resulting in uncontrolled cell proliferation and survival (Lee2013The; Gäbler2013JAK2). This mutation is found in over 95% of PV cases and 50%-60% of ET and PMF cases (Morgan2008A; Downes2022JAK2).

The JAK2V617F mutation occurs in the pseudokinase domain, disrupting its autoinhibitory function and leading to continuous kinase activity (James2005A). This mutation is also implicated in other hematological malignancies, such as chronic myelomonocytic leukemia and acute myeloid leukemia (AML) (Lee2013The; Morgan2008A). Additionally, JAK2 mutations are associated with the high-risk Ph-like acute lymphoblastic leukemia (ALL) subtype (Downes2022JAK2).

JAK2 mutations can also lead to homozygosity through mitotic recombination, which is linked to more severe disease phenotypes (Morgan2008A). The presence of these mutations highlights the potential for targeted therapies, such as JAK inhibitors, in treating these conditions (Lee2013The; Gäbler2013JAK2).

## Interactions
JAK2 interacts with the growth hormone receptor (GHR) to form a complex that is crucial for signal transduction. Upon growth hormone (GH) binding, JAK2 associates with GHR, leading to the phosphorylation of both JAK2 and GHR, which is essential for the activation of downstream signaling pathways (Argetsinger1993Identification). This interaction is part of a broader signaling mechanism shared among members of the cytokine/hematopoietin receptor family (Argetsinger1993Identification).

JAK2 is also regulated by the ubiquitin-proteasome pathway, where it interacts with SOCS-1 (Suppressor of Cytokine Signaling 1). SOCS-1 binds to JAK2, promoting its polyubiquitination and subsequent degradation, a process dependent on the phosphorylation of JAK2 at tyrosine 1007 (Ungureanu2002Regulation). This interaction is crucial for controlling JAK2 activity and maintaining cellular homeostasis.

Additionally, JAK2's kinase activity is inhibited by the JAK-binding protein (JAB), which binds to the activation loop of JAK2 through its SH2 domain and a kinase inhibitory region. This binding prevents substrate and ATP access to the catalytic pocket, effectively inhibiting JAK2's kinase activity (Yasukawa1999The).


## References


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[2. (Shahi2022The) Aashirwad Shahi, Jacob Kahle, Chandler Hopkins, and Maria Diakonova. The sh2 domain and kinase activity of jak2 target jak2 to centrosome and regulate cell growth and centrosome amplification. PLOS ONE, 17(1):e0261098, January 2022. URL: http://dx.doi.org/10.1371/journal.pone.0261098, doi:10.1371/journal.pone.0261098. This article has 1 citations and is from a peer-reviewed journal.](https://doi.org/10.1371/journal.pone.0261098)

[3. (Gäbler2013JAK2) Karoline Gäbler, Iris Behrmann, and Claude Haan. Jak2 mutants (e.g., jak2v617f) and their importance as drug targets in myeloproliferative neoplasms. JAK-STAT, 2(3):e25025, July 2013. URL: http://dx.doi.org/10.4161/jkst.25025, doi:10.4161/jkst.25025. This article has 20 citations.](https://doi.org/10.4161/jkst.25025)

[4. (Argetsinger1993Identification) Lawrence S. Argetsinger, George S. Campbell, Xianjie Yang, Bruce A. Witthuhn, Olli Silvennoinen, James N. Ihle, and Christin Carter-Su. Identification of jak2 as a growth hormone receptor-associated tyrosine kinase. Cell, 74(2):237–244, July 1993. URL: http://dx.doi.org/10.1016/0092-8674(93)90415-m, doi:10.1016/0092-8674(93)90415-m. This article has 692 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/0092-8674(93)90415-m)

[5. (Sandberg2004Jak2) Eric M. Sandberg, Tiffany A. Wallace, Michael D. Godeny, Danielle VonDerLinden, and Peter P. Sayeski. Jak2 tyrosine kinase: a true jak of all trades? Cell Biochemistry and Biophysics, 41(2):207–232, 2004. URL: http://dx.doi.org/10.1385/cbb:41:2:207, doi:10.1385/cbb:41:2:207. This article has 36 citations and is from a peer-reviewed journal.](https://doi.org/10.1385/cbb:41:2:207)

[6. (Perner2019Roles) Florian Perner, Caroline Perner, Thomas Ernst, and Florian H. Heidel. Roles of jak2 in aging, inflammation, hematopoiesis and malignant transformation. Cells, 8(8):854, August 2019. URL: http://dx.doi.org/10.3390/cells8080854, doi:10.3390/cells8080854. This article has 139 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/cells8080854)

[7. (Ihle2007Jak2:) James N Ihle and D Gary Gilliland. Jak2: normal function and role in hematopoietic disorders. Current Opinion in Genetics & Development, 17(1):8–14, February 2007. URL: http://dx.doi.org/10.1016/j.gde.2006.12.009, doi:10.1016/j.gde.2006.12.009. This article has 111 citations.](https://doi.org/10.1016/j.gde.2006.12.009)

[8. (Lindauer2001Prediction) Klaus Lindauer, Thomas Loerting, Klaus R. Liedl, and Romano T. Kroemer. Prediction of the structure of human janus kinase 2 (jak2) comprising the two carboxy-terminal domains reveals a mechanism for autoregulation. Protein Engineering, Design and Selection, 14(1):27–37, January 2001. URL: http://dx.doi.org/10.1093/protein/14.1.27, doi:10.1093/protein/14.1.27. This article has 132 citations.](https://doi.org/10.1093/protein/14.1.27)

[9. (Yasukawa1999The) H. Yasukawa. The jak-binding protein jab inhibits janus tyrosine kinase activity through binding in the activation loop. The EMBO Journal, 18(5):1309–1320, March 1999. URL: http://dx.doi.org/10.1093/emboj/18.5.1309, doi:10.1093/emboj/18.5.1309. This article has 561 citations.](https://doi.org/10.1093/emboj/18.5.1309)

[10. (Wan2013Ab) Xiaobo Wan, Yue Ma, Christopher L. McClendon, Lily Jun-shen Huang, and Niu Huang. Ab initio modeling and experimental assessment of janus kinase 2 (jak2) kinase-pseudokinase complex structure. PLoS Computational Biology, 9(4):e1003022, April 2013. URL: http://dx.doi.org/10.1371/journal.pcbi.1003022, doi:10.1371/journal.pcbi.1003022. This article has 10 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1371/journal.pcbi.1003022)

[11. (Downes2022JAK2) Charlotte EJ. Downes, Barbara J. McClure, Daniel P. McDougal, Susan L. Heatley, John B. Bruning, Daniel Thomas, David T. Yeung, and Deborah L. White. Jak2 alterations in acute lymphoblastic leukemia: molecular insights for superior precision medicine strategies. Frontiers in Cell and Developmental Biology, July 2022. URL: http://dx.doi.org/10.3389/fcell.2022.942053, doi:10.3389/fcell.2022.942053. This article has 17 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fcell.2022.942053)

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[13. (Lee2013The) Hun Ju Lee, Naval Daver, Hagop M. Kantarjian, Srdan Verstovsek, and Farhad Ravandi. The role of jak pathway dysregulation in the pathogenesis and treatment of acute myeloid leukemia. Clinical Cancer Research, 19(2):327–335, January 2013. URL: http://dx.doi.org/10.1158/1078-0432.ccr-12-2087, doi:10.1158/1078-0432.ccr-12-2087. This article has 38 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1158/1078-0432.ccr-12-2087)

[14. (James2005A) Chloé James, Valérie Ugo, Nicole Casadevall, Stefan N. Constantinescu, and William Vainchenker. A jak2 mutation in myeloproliferative disorders: pathogenesis and therapeutic and scientific prospects. Trends in Molecular Medicine, 11(12):546–554, December 2005. URL: http://dx.doi.org/10.1016/j.molmed.2005.10.003, doi:10.1016/j.molmed.2005.10.003. This article has 87 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/j.molmed.2005.10.003)

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[17. (Giordanetto2002Prediction) Fabrizio Giordanetto and Romano T. Kroemer. Prediction of the structure of human janus kinase 2 (jak2) comprising jak homology domains 1 through 7. Protein Engineering, Design and Selection, 15(9):727–737, September 2002. URL: http://dx.doi.org/10.1093/protein/15.9.727, doi:10.1093/protein/15.9.727. This article has 71 citations.](https://doi.org/10.1093/protein/15.9.727)