JAK3 (Janus Kinase 3 or Just Another Kinase 3)
2007-07-01 Ping Shi , Hesham M Amin AffiliationDepartment of Hematopathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
Identity
HGNC
LOCATION
19p13.11
LOCUSID
ALIAS
JAK-3,JAK3_HUMAN,JAKL,L-JAK,LJAK
FUSION GENES
DNA/RNA
Description
JAK3 is a functioning gene that comprises 23 exons spanning roughly 21 kb of genomic DNA with an open reading frame of 3372 bp.
Transcription
4025 bp mRNA. 7 transcript variants encoding 7 distinct proteins.
Proteins
Note
3 isoforms produced by alternative splicing: JAK3S, JAK3B, JAK3M.
Description
1124 amino acids, 125099 Da. JAK3 is comprised of 7 JAK homology (JH) domains. JH1 contains the C terminus kinase domain and an SH2 or SH3 binding motif; JH2 contains a pseudokinase domain tandemly linked to the N site of the JH1 domain; 5 more JH domains. The N terminus region (JH6 and JH7) is critical for receptor binding and signal transduction.
Expression
JAK3 is expressed in 12 normal human tissues (bone marrow, spleen, thymus, brain, spinal cord, heart, skeletal muscle, liver, pancreas, prostate, kidney, and lung). JAK3S is more commonly seen in hematopoietic cells, whereas JAK3B and JAK3M are detected in cells of hematopoietic or epithelial origin.
Localisation
Intracellular, membrane-associated through association with interleukin (IL) receptor common gamma chain (gamma-c).
Function
Tyrosine kinase of the non-receptor type. Involved in the signaling of ILs that contain the gamma-c chain in their respective receptors, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Induces tyrosine phosphorylation of a number of proteins, of which most widely studied are signal transducers and activators of transcriptions (STAT). JAK3 has also been shown to phosphorylate insulin receptor substrate-1 (IRS-1), IRS-2, and PI3K/Akt.
Mutations
Note
Mostly point mutations were identified affecting all 7 structural JH domains of JAK3.
Different mutations identified in all of the 7 domains of JAK3. The mutations in "black color" are the mutations reported in JAK3-SCID; "red color and italic" identifies mutations reported in acute megakaryoblastic leukemia; and "orange color and underline" highlights one mutation that has been reported in both JAK3-SCID and acute megakaryoblastic leukemia.
Somatic
Mutations of JAK3 were generally associated with the same cellular phenotype of the more frequently encountered X-linked SCID due to gamma-c deficiency. It was confirmed with the identification of 34 mutations in JAK3-SCID patients from Europe and the US. JAK3-SCID is inherited as autosomal recessive disease. It is estimated to account for approximately 7-14% of heritable SCID. JAK3 mutations are seemingly sporadic, and neither preferential gene locations (i.e. gene "hot-spots") nor founder effects have yet been documented.
The majority of JAK3-SCID patients are compound heterozygotes, having inherited a distinct mutation from each parent, although some individuals are homozygous for their mutations as a result of parental consanguinity. Most mutations have dramatic effects on protein expression of JAK3, but some missense mutations or small in-frame deletions allow for some protein expression. These mutations affect kinase activity, receptor binding, and intracellular trafficking.
In addition, 7 mutations of JAK3 have been recently described in 5 patients with acute megakaryoblastic leukemia with or without Down syndrome. These mutations are in general activation mutations. The Down syndrome patients presented initially with transient TXT: myeloproliferative disease.
The majority of JAK3-SCID patients are compound heterozygotes, having inherited a distinct mutation from each parent, although some individuals are homozygous for their mutations as a result of parental consanguinity. Most mutations have dramatic effects on protein expression of JAK3, but some missense mutations or small in-frame deletions allow for some protein expression. These mutations affect kinase activity, receptor binding, and intracellular trafficking.
In addition, 7 mutations of JAK3 have been recently described in 5 patients with acute megakaryoblastic leukemia with or without Down syndrome. These mutations are in general activation mutations. The Down syndrome patients presented initially with transient TXT: myeloproliferative disease.
Implicated in
Entity name
Severe combined immunodeficiency (SCID)
Note
34 unique mutations of JAK3 have been identified in cases of JAK3-SCID, occurring in all of its 7 structural JH domains. No hotspots have been reported and multiple types of mutations have been identified: 21 missense/nonsense mutations, 7 splice site mutations, 3 small deletions, 2 gross deletions and 1 insertion.
Disease
Defects in JAK3 are associated with the autosomal recessive T-cell negative/B-cell positive type of severe combined immunodeficiency (SCID); a condition characterized by the absence of circulating mature T-lymphocytes and NK cells, normal to elevated numbers of nonfunctional B-lymphocytes, and marked hypoplasia of lymphoid tissues.
Prognosis
SCID due to JAK3 deficiency is generally a lethal disorder. The advent of hematopoietic stem cell transplant revolutionized the outcome of JAK3-SCID, and at present it is still the treatment of choice.
Entity name
Note
7 unique mutations of JAK3 have also been identified in patients with acute megakaryoblastic leukemia. These mutations occur in the JH2, JH6, and JH7 domains.
Disease
Also, defects in JAK3 have been recently described in some cases of acute megakaryoblastic leukemia with or without Down syndrome. Acute megakaryoblastic leukemia is a type of acute leukemia where more than 50% of the blasts are of megakaryocytic lineage. The exact role of JAK3 in this disease is not completely known.
Prognosis
Acute megakaryoblastic leukemia demonstrates a bad clinical outcome.
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 9753072 | 1998 | Molecular and biochemical characterization of JAK3 deficiency in a patient with severe combined immunodeficiency over 20 years after bone marrow transplantation: implications for treatment. | Bozzi F et al |
| 10573019 | 1999 | Revised exon-intron structure of human JAK3 locus. | Brooimans RA et al |
| 10021471 | 1999 | Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. | Buckley RH et al |
| 9354668 | 1997 | Structural and functional basis for JAK3-deficient severe combined immunodeficiency. | Candotti F et al |
| 16790275 | 2007 | Identification of a constitutively active mutant of JAK3 by retroviral expression screening. | Choi YL et al |
| 11133738 | 2001 | Interleukin 15: biology and relevance to human disease. | Fehniger TA et al |
| 11253129 | 2001 | Diagnosis of severe combined immunodeficiency. | Gennery AR et al |
| 15057824 | 2004 | The DNA sequence and biology of human chromosome 19. | Grimwood J et al |
| 16825495 | 2006 | Loss of SHP1 enhances JAK3/STAT3 signaling and decreases proteosome degradation of JAK3 and NPM-ALK in ALK+ anaplastic large-cell lymphoma. | Han Y et al |
| 7499365 | 1995 | Interleukins 2, 4, 7, and 15 stimulate tyrosine phosphorylation of insulin receptor substrates 1 and 2 in T cells. Potential role of JAK kinases. | Johnston JA et al |
| 8022790 | 1994 | Molecular cloning of L-JAK, a Janus family protein-tyrosine kinase expressed in natural killer cells and activated leukocytes. | Kawamura M et al |
| 17252020 | 2007 | JAK3 mutations occur in acute megakaryoblastic leukemia both in Down syndrome children and non-Down syndrome adults. | Kiyoi H et al |
| 16932349 | 2006 | Jak3- and JNK-dependent vascular endothelial growth factor expression in cutaneous T-cell lymphoma. | Krejsgaard T et al |
| 7659163 | 1995 | Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). | Macchi P et al |
| 15621777 | 2005 | Activation of the Jak3 pathway and myeloid differentiation. | Mangan JK et al |
| 17433830 | 2007 | A novel mutation of intron 22 in Janus kinase 3-deficient severe combined immunodeficiency. | Mjaanes CM et al |
| 16308103 | 2005 | Differential expression of Janus kinase 3 (JAK3), matrix metalloproteinase 13 (MMP13), heat shock protein 60 (HSP60), and mouse double minute 2 (MDM2) in human colorectal cancer progression using human cancer cDNA microarrays. | Mori D et al |
| 15220007 | 2004 | Jak3 and the pathogenesis of severe combined immunodeficiency. | O'Shea JJ et al |
| 15661026 | 2005 | Jak3, severe combined immunodeficiency, and a new class of immunosuppressive drugs. | Pesu M et al |
| 16763206 | 2006 | Autocrine release of interleukin-9 promotes Jak3-dependent survival of ALK+ anaplastic large-cell lymphoma cells. | Qiu L et al |
| 7518579 | 1994 | JAK3: a novel JAK kinase associated with terminal differentiation of hematopoietic cells. | Rane SG et al |
| 8921370 | 1996 | Genomic sequence, organization, and chromosomal localization of human JAK3. | Riedy MC et al |
| 14615376 | 2004 | Janus kinase 3 (JAK3) deficiency: clinical, immunologic, and molecular analyses of 10 patients and outcomes of stem cell transplantation. | Roberts JL et al |
| 7481768 | 1995 | Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. | Russell SM et al |
| 10982185 | 2000 | Complete genomic organization of the human JAK3 gene and mutation analysis in severe combined immunodeficiency by single-strand conformation polymorphism. | Schumacher RF et al |
| 10900158 | 2000 | Molecular modeling of the Jak3 kinase domains and structural basis for severe combined immunodeficiency. | Vihinen M et al |
| 16843266 | 2006 | Activating alleles of JAK3 in acute megakaryoblastic leukemia. | Walters DK et al |
| 15575979 | 2004 | The Janus kinases (Jaks). | Yamaoka K et al |
Other Information
Locus ID:
NCBI: 3718
MIM: 600173
HGNC: 6193
Ensembl: ENSG00000105639
Variants:
dbSNP: 3718
ClinVar: 3718
TCGA: ENSG00000105639
COSMIC: JAK3
RNA/Proteins
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 37876297 | 2024 | Dependence of peripheral T-cell lymphoma on constitutively activated JAK3: Implication for JAK3 inhibition as a therapeutic approach. | 1 |
| 38474223 | 2024 | Janus Kinase 3 (JAK3): A Critical Conserved Node in Immunity Disrupted in Immune Cell Cancer and Immunodeficiency. | 0 |
| 38598033 | 2024 | Omenn Syndrome in Two Infants with Different Hypomorphic Variants in Janus Kinase 3. | 0 |
| 37876297 | 2024 | Dependence of peripheral T-cell lymphoma on constitutively activated JAK3: Implication for JAK3 inhibition as a therapeutic approach. | 1 |
| 38474223 | 2024 | Janus Kinase 3 (JAK3): A Critical Conserved Node in Immunity Disrupted in Immune Cell Cancer and Immunodeficiency. | 0 |
| 38598033 | 2024 | Omenn Syndrome in Two Infants with Different Hypomorphic Variants in Janus Kinase 3. | 0 |
| 37830594 | 2023 | New JAK3-INSL3 Fusion Transcript-An Oncogenic Event in Cutaneous T-Cell Lymphoma. | 2 |
| 38095643 | 2023 | Conjoint research of WGCNA, single-cell transcriptome and structural biology reveals the potential targets of IDD development and treatment and JAK3 involvement. | 0 |
| 37830594 | 2023 | New JAK3-INSL3 Fusion Transcript-An Oncogenic Event in Cutaneous T-Cell Lymphoma. | 2 |
| 38095643 | 2023 | Conjoint research of WGCNA, single-cell transcriptome and structural biology reveals the potential targets of IDD development and treatment and JAK3 involvement. | 0 |
| 35411095 | 2022 | JAK3 mutations and mitochondrial apoptosis resistance in T-cell acute lymphoblastic leukemia. | 4 |
| 36100323 | 2022 | Prognostic value of JAK3 promoter methylation and mRNA expression in clear cell renal cell carcinoma. | 3 |
| 36291730 | 2022 | Zebrafish Model of Severe Combined Immunodeficiency (SCID) Due to JAK3 Mutation. | 4 |
| 35411095 | 2022 | JAK3 mutations and mitochondrial apoptosis resistance in T-cell acute lymphoblastic leukemia. | 4 |
| 36100323 | 2022 | Prognostic value of JAK3 promoter methylation and mRNA expression in clear cell renal cell carcinoma. | 3 |
Citation
Ping Shi ; Hesham M Amin
JAK3 (Janus Kinase 3 or Just Another Kinase 3)
Atlas Genet Cytogenet Oncol Haematol. 2007-07-01
Online version: http://atlasgeneticsoncology.org/gene/41032
