JAK3 (Janus Kinase 3 or Just Another Kinase 3)

2007-07-01   Ping Shi , Hesham M Amin 

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA





JAK3 is a functioning gene that comprises 23 exons spanning roughly 21 kb of genomic DNA with an open reading frame of 3372 bp.


4025 bp mRNA. 7 transcript variants encoding 7 distinct proteins.



3 isoforms produced by alternative splicing: JAK3S, JAK3B, JAK3M.


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.


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.


Intracellular, membrane-associated through association with interleukin (IL) receptor common gamma chain (gamma-c).


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.


JAK3 is the most recently identified member of the mammalian Janus kinase subfamily (TYK2, JAK1, JAK2, and JAK3); JAK3 paralogs to JAK1 and JAK2; human JAK3 orthologs to murine Jak3.



Mostly point mutations were identified affecting all 7 structural JH domains of JAK3.
Atlas Image
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.


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.

Implicated in

Entity name
Severe combined immunodeficiency (SCID)
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.
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.
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.
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.
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.
Acute megakaryoblastic leukemia demonstrates a bad clinical outcome.


Pubmed IDLast YearTitleAuthors
97530721998Molecular 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
105730191999Revised exon-intron structure of human JAK3 locus.Brooimans RA et al
100214711999Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency.Buckley RH et al
93546681997Structural and functional basis for JAK3-deficient severe combined immunodeficiency.Candotti F et al
167902752007Identification of a constitutively active mutant of JAK3 by retroviral expression screening.Choi YL et al
111337382001Interleukin 15: biology and relevance to human disease.Fehniger TA et al
112531292001Diagnosis of severe combined immunodeficiency.Gennery AR et al
150578242004The DNA sequence and biology of human chromosome 19.Grimwood J et al
168254952006Loss 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
74993651995Interleukins 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
80227901994Molecular cloning of L-JAK, a Janus family protein-tyrosine kinase expressed in natural killer cells and activated leukocytes.Kawamura M et al
172520202007JAK3 mutations occur in acute megakaryoblastic leukemia both in Down syndrome children and non-Down syndrome adults.Kiyoi H et al
169323492006Jak3- and JNK-dependent vascular endothelial growth factor expression in cutaneous T-cell lymphoma.Krejsgaard T et al
76591631995Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID).Macchi P et al
156217772005Activation of the Jak3 pathway and myeloid differentiation.Mangan JK et al
174338302007A novel mutation of intron 22 in Janus kinase 3-deficient severe combined immunodeficiency.Mjaanes CM et al
163081032005Differential 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
152200072004Jak3 and the pathogenesis of severe combined immunodeficiency.O'Shea JJ et al
156610262005Jak3, severe combined immunodeficiency, and a new class of immunosuppressive drugs.Pesu M et al
167632062006Autocrine release of interleukin-9 promotes Jak3-dependent survival of ALK+ anaplastic large-cell lymphoma cells.Qiu L et al
75185791994JAK3: a novel JAK kinase associated with terminal differentiation of hematopoietic cells.Rane SG et al
89213701996Genomic sequence, organization, and chromosomal localization of human JAK3.Riedy MC et al
146153762004Janus kinase 3 (JAK3) deficiency: clinical, immunologic, and molecular analyses of 10 patients and outcomes of stem cell transplantation.Roberts JL et al
74817681995Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development.Russell SM et al
109821852000Complete genomic organization of the human JAK3 gene and mutation analysis in severe combined immunodeficiency by single-strand conformation polymorphism.Schumacher RF et al
109001582000Molecular modeling of the Jak3 kinase domains and structural basis for severe combined immunodeficiency.Vihinen M et al
168432662006Activating alleles of JAK3 in acute megakaryoblastic leukemia.Walters DK et al
155759792004The Janus kinases (Jaks).Yamaoka K et al

Other Information

Locus ID:

NCBI: 3718
MIM: 600173
HGNC: 6193
Ensembl: ENSG00000105639


dbSNP: 3718
ClinVar: 3718
TCGA: ENSG00000105639


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Jak-STAT signaling pathwayKEGGko04630
Non-small cell lung cancerKEGGko05223
Primary immunodeficiencyKEGGko05340
Jak-STAT signaling pathwayKEGGhsa04630
Non-small cell lung cancerKEGGhsa05223
Primary immunodeficiencyKEGGhsa05340
Chemokine signaling pathwayKEGGko04062
Chemokine signaling pathwayKEGGhsa04062
HTLV-I infectionKEGGko05166
HTLV-I infectionKEGGhsa05166
Epstein-Barr virus infectionKEGGhsa05169
Epstein-Barr virus infectionKEGGko05169
Viral carcinogenesisKEGGhsa05203
Viral carcinogenesisKEGGko05203
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
Signaling pathways regulating pluripotency of stem cellsKEGGhsa04550
Signaling pathways regulating pluripotency of stem cellsKEGGko04550
JAK-STAT signalingKEGGhsa_M00684
JAK-STAT signalingKEGGM00684
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491
RAF/MAP kinase cascadeREACTOMER-HSA-5673001
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
FCERI mediated MAPK activationREACTOMER-HSA-2871796
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-2 signalingREACTOMER-HSA-451927
Interleukin receptor SHC signalingREACTOMER-HSA-912526
Interleukin-3, 5 and GM-CSF signalingREACTOMER-HSA-512988
Interleukin-7 signalingREACTOMER-HSA-1266695
Platelet activation, signaling and aggregationREACTOMER-HSA-76002
GPVI-mediated activation cascadeREACTOMER-HSA-114604
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
GRB2 events in EGFR signalingREACTOMER-HSA-179812
SHC1 events in EGFR signalingREACTOMER-HSA-180336
Signaling by Insulin receptorREACTOMER-HSA-74752
Insulin receptor signalling cascadeREACTOMER-HSA-74751
IRS-mediated signallingREACTOMER-HSA-112399
SOS-mediated signallingREACTOMER-HSA-112412
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
Signalling to ERKsREACTOMER-HSA-187687
Signalling to RASREACTOMER-HSA-167044
Signalling to p38 via RIT and RINREACTOMER-HSA-187706
Prolonged ERK activation eventsREACTOMER-HSA-169893
Frs2-mediated activationREACTOMER-HSA-170968
ARMS-mediated activationREACTOMER-HSA-170984
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by VEGFREACTOMER-HSA-194138
VEGFR2 mediated cell proliferationREACTOMER-HSA-5218921
Signaling by SCF-KITREACTOMER-HSA-1433557
MAPK family signaling cascadesREACTOMER-HSA-5683057
MAPK1/MAPK3 signalingREACTOMER-HSA-5684996
Signaling by GPCRREACTOMER-HSA-372790
GPCR downstream signalingREACTOMER-HSA-388396
G-protein beta:gamma signallingREACTOMER-HSA-397795
G beta:gamma signalling through PI3KgammaREACTOMER-HSA-392451
Gastrin-CREB signalling pathway via PKC and MAPKREACTOMER-HSA-881907
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)REACTOMER-HSA-2404192
IGF1R signaling cascadeREACTOMER-HSA-2428924
IRS-related events triggered by IGF1RREACTOMER-HSA-2428928
Signaling by LeptinREACTOMER-HSA-2586552
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
NCAM signaling for neurite out-growthREACTOMER-HSA-375165
RET signalingREACTOMER-HSA-8853659
Th1 and Th2 cell differentiationKEGGko04658
Th1 and Th2 cell differentiationKEGGhsa04658
Th17 cell differentiationKEGGko04659
Th17 cell differentiationKEGGhsa04659
Interleukin-4 and 13 signalingREACTOMER-HSA-6785807

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
194704742009JAK mutations in high-risk childhood acute lymphoblastic leukemia.195
76591631995Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID).162
79736581994Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3: implications for XSCID and XCID.140
145931822003Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor.139
80224851994Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2.125
168432662006Activating alleles of JAK3 in acute megakaryoblastic leukemia.115
190177632009Enhanced expression of Janus kinase-signal transducer and activator of transcription pathway members in human diabetic nephropathy.107
123516252002The pseudokinase domain is required for suppression of basal activity of Jak2 and Jak3 tyrosine kinases and for cytokine-inducible activation of signal transduction.85
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
223682722012Outcome modeling with CRLF2, IKZF1, JAK, and minimal residual disease in pediatric acute lymphoblastic leukemia: a Children's Oncology Group study.79


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/jak3-(janus-kinase-3-or-just-another-kinase-3)