Januskinase 1

Last updated on: 11.07.2021

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Janus kinase 1 is a membrane protein that belongs to a class of protein tyrosine kinases (PTK) (Janus kinases). Janus kinase 1 is encoded by the gene of the same name located on chromosome 1p31.3. The encoded kinase (JAK1) phosphorylates STAT proteins (Signal Transducers and Activators of Transcription) and plays a key role in interferon-alpha/beta, interferon-gamma and cytokine signal transduction.

General information
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The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway plays an important oncogenic role in myeloproliferative neoplasms (MPNs) and acute lymphoblastic leukemia (ALL).

In normal cells, cytokine-induced activation of the JAK/STAT pathway stimulates proliferation, survival, differentiation, and functional activation, resulting in tightly regulated, on-demand blood cell production (Vainchenker W et al. 2013).

JAK1 - kinase occupies a key position in the interleukin-6 (IL-6)/JAK1/STAT3 immune and inflammatory response and is a therapeutic target in inflammatory systemic responses. The activity of this gene is directly inhibited by the protein "Suppressor of Cytokine Signalling 1 -SOCS1-".

JAK1 is highly expressed in lymphoid and myeloid cell lines, especially granulocytes, but is poorly expressed in megakaryocyte-erythroid progenitors (MEPs) and their progeny compared to JAK2. Gain-of-function mutations lead to proliferation of myeloid cells rather than erythroid cells or platelets.

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Activating mutations of JAK1 have been reported primarily in prolymphocytic T-cell leukemia(Bellanger D et al.2014) and acute lymphoblastic leukemia (Mullighan CG et al. 2009), where they have been shown to lead to a worse prognosis. Transduction of the V658F, V658L and V658I variants of JAK1 results in factor-independent cell growth of BaF3 cells, whereas transduction of wild-type JAK1 does not ,17 so the mutation is undoubtedly pathogenic. The increased enzyme activity triggers uncontrolled proliferation of lymphoid progenitor cells. Loss-of-function mutations of JAK1 occur with high frequency in tumors with microsatellite instability and may contribute to tumor immune evasion.

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  1. Baxter EJ et al (2005) Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 365:1054-1061.
  2. Bellanger D et al.(2014) Recurrent JAK1 and JAK3 somatic mutations in T-cell prolymphocytic leukemia. Leukemia 28:417-419.
  3. Gordon GM et al.(2010) Transforming JAK1 mutations exhibit differential signalling, FERM domain requirements and growth responses to interferon-γ. Biochem J 432:255-265.
  4. James C et al.(2005) A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434:1144-1148.
  5. Kralovics R et al.(2005) A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 352:1779-1790.
  6. Levine RL et al.(2005) Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 7:387-397.
  7. Mullighan CG et al.(2009) JAK mutations in high-risk childhood acute lymphoblastic leukemia. Proc Natl Acad Sci USA 106:9414-9418.
  8. Vainchenker W et al.(2013) JAK/STAT signaling in hematological malignancies. Oncogene 32:2601-2613.

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Januskinase 2;

Last updated on: 11.07.2021