Janus Kinase 3 (JAK3): A Critical Conserved Node in Immunity Disrupted in Immune Cell Cancer and Immunodeficiency

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2024 Mar 13

PMID 38474223

Authors

Clifford Liongue

Tarindhi Ratnayake

Faiza Basheer

Alister C Ward

Affiliations

Soon will be listed here.

Abstract

The Janus kinase (JAK) family is a small group of protein tyrosine kinases that represent a central component of intracellular signaling downstream from a myriad of cytokine receptors. The JAK3 family member performs a particularly important role in facilitating signal transduction for a key set of cytokine receptors that are essential for immune cell development and function. Mutations that impact JAK3 activity have been identified in a number of human diseases, including somatic gain-of-function (GOF) mutations associated with immune cell malignancies and germline loss-of-function (LOF) mutations associated with immunodeficiency. The structure, function and impacts of both GOF and LOF mutations of JAK3 are highly conserved, making animal models highly informative. This review details the biology of JAK3 and the impact of its perturbation in immune cell-related diseases, including relevant animal studies.

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References

Rivera-Munoz P, Laurent A, Siret A, Lopez C, Ignacimouttou C, Cornejo M . Partial trisomy 21 contributes to T-cell malignancies induced by JAK3-activating mutations in murine models. Blood Adv. 2018; 2(13):1616-1627. PMC: 6039658. DOI: 10.1182/bloodadvances.2018016089. View

Lin J, Leonard W . The Common Cytokine Receptor γ Chain Family of Cytokines. Cold Spring Harb Perspect Biol. 2017; 10(9). PMC: 6120701. DOI: 10.1101/cshperspect.a028449. View

Losdyck E, Hornakova T, Springuel L, Degryse S, Gielen O, Cools J . Distinct Acute Lymphoblastic Leukemia (ALL)-associated Janus Kinase 3 (JAK3) Mutants Exhibit Different Cytokine-Receptor Requirements and JAK Inhibitor Specificities. J Biol Chem. 2015; 290(48):29022-34. PMC: 4661414. DOI: 10.1074/jbc.M115.670224. View

Malinge S, Ragu C, Della-Valle V, Pisani D, Constantinescu S, Perez C . Activating mutations in human acute megakaryoblastic leukemia. Blood. 2008; 112(10):4220-6. DOI: 10.1182/blood-2008-01-136366. View

Sertori R, Jones R, Basheer F, Rivera L, Dawson S, Loke S . Generation and Characterization of a Zebrafish IL-2Rγc SCID Model. Int J Mol Sci. 2022; 23(4). PMC: 8875600. DOI: 10.3390/ijms23042385. View

Noguchi M, Yi H, Rosenblatt H, Filipovich A, Adelstein S, Modi W . Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell. 1993; 73(1):147-57. DOI: 10.1016/0092-8674(93)90167-o. View

Witthuhn B, Silvennoinen O, Miura O, Lai K, Cwik C, Liu E . Involvement of the Jak-3 Janus kinase in signalling by interleukins 2 and 4 in lymphoid and myeloid cells. Nature. 1994; 370(6485):153-7. DOI: 10.1038/370153a0. View

Cornejo M, Kharas M, Werneck M, Le Bras S, Moore S, Ball B . Constitutive JAK3 activation induces lymphoproliferative syndromes in murine bone marrow transplantation models. Blood. 2009; 113(12):2746-54. PMC: 2661862. DOI: 10.1182/blood-2008-06-164368. View

Yamashita Y, Yuan J, Suetake I, Suzuki H, Ishikawa Y, Choi Y . Array-based genomic resequencing of human leukemia. Oncogene. 2010; 29(25):3723-31. DOI: 10.1038/onc.2010.117. View

10.

Raivola J, Hammaren H, Virtanen A, Bulleeraz V, Ward A, Silvennoinen O . Hyperactivation of Oncogenic JAK3 Mutants Depend on ATP Binding to the Pseudokinase Domain. Front Oncol. 2018; 8:560. PMC: 6287396. DOI: 10.3389/fonc.2018.00560. View

11.

Kiel M, Velusamy T, Rolland D, Sahasrabuddhe A, Chung F, Bailey N . Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia. Blood. 2014; 124(9):1460-72. PMC: 4148768. DOI: 10.1182/blood-2014-03-559542. View

12.

Marciano B, Huang C, Joshi G, Rezaei N, Carvalho B, Allwood Z . BCG vaccination in patients with severe combined immunodeficiency: complications, risks, and vaccination policies. J Allergy Clin Immunol. 2014; 133(4):1134-41. PMC: 4015464. DOI: 10.1016/j.jaci.2014.02.028. View

13.

Nairismagi M, Gerritsen M, Li Z, Wijaya G, Chia B, Laurensia Y . Oncogenic activation of JAK3-STAT signaling confers clinical sensitivity to PRN371, a novel selective and potent JAK3 inhibitor, in natural killer/T-cell lymphoma. Leukemia. 2018; 32(5):1147-1156. PMC: 5940653. DOI: 10.1038/s41375-017-0004-x. View

14.

Yuan S, Wang X, Hou S, Guo T, Lan Y, Yang S . PHF6 and JAK3 mutations cooperate to drive T-cell acute lymphoblastic leukemia progression. Leukemia. 2021; 36(2):370-382. PMC: 8807395. DOI: 10.1038/s41375-021-01392-1. View

15.

Bouchekioua A, Scourzic L, De Wever O, Zhang Y, Cervera P, Aline-Fardin A . JAK3 deregulation by activating mutations confers invasive growth advantage in extranodal nasal-type natural killer cell lymphoma. Leukemia. 2013; 28(2):338-48. DOI: 10.1038/leu.2013.157. View

16.

He Y, Malek T . Interleukin-7 receptor alpha is essential for the development of gamma delta + T cells, but not natural killer cells. J Exp Med. 1996; 184(1):289-93. PMC: 2192680. DOI: 10.1084/jem.184.1.289. View

17.

Roifman C, Zhang J, Chitayat D, Sharfe N . A partial deficiency of interleukin-7R alpha is sufficient to abrogate T-cell development and cause severe combined immunodeficiency. Blood. 2000; 96(8):2803-7. View

18.

Basheer F, Lee E, Liongue C, Ward A . Zebrafish Model of Severe Combined Immunodeficiency (SCID) Due to JAK3 Mutation. Biomolecules. 2022; 12(10). PMC: 9599616. DOI: 10.3390/biom12101521. View

19.

Sic H, Speletas M, Cornacchione V, Seidl M, Beibel M, Linghu B . An Activating Janus Kinase-3 Mutation Is Associated with Cytotoxic T Lymphocyte Antigen-4-Dependent Immune Dysregulation Syndrome. Front Immunol. 2018; 8:1824. PMC: 5770691. DOI: 10.3389/fimmu.2017.01824. View

20.

Peschon J, Morrissey P, Grabstein K, Ramsdell F, Maraskovsky E, Gliniak B . Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J Exp Med. 1994; 180(5):1955-60. PMC: 2191751. DOI: 10.1084/jem.180.5.1955. View