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JAK3 (Janus Kinase 3 or Just Another Kinase 3)

Identity

Other namesJAK-3
JAK_HUMAN
L-JAK
LJAK
EC 2.7.10.2
HGNC (Hugo) JAK3
LocusID (NCBI) 3718
Location 19p13.11
Location_base_pair Starts at 17935593 and ends at 17958841 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order chr19: 17788,324-17819800

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.

Protein

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.
Homology 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.

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.

Implicated in

Entity 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 Acute megakaryoblastic leukemia
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.
  

External links

Nomenclature
HGNC (Hugo)JAK3   6193
Cards
AtlasJAK3ID41032ch19p13
Entrez_Gene (NCBI)JAK3  3718  Janus kinase 3
GeneCards (Weizmann)JAK3
Ensembl (Hinxton)ENSG00000105639 [Gene_View]  chr19:17935593-17958841 [Contig_View]  JAK3 [Vega]
AceView (NCBI)JAK3
Genatlas (Paris)JAK3
WikiGenes3718
SOURCE (Princeton)NM_000215
Genomic and cartography
GoldenPath (UCSC)JAK3  -  19p13.11   chr19:17935593-17958841 -  19p13-p12   [Description]    (hg19-Feb_2009)
EnsemblJAK3 - 19p13-p12 [CytoView]
Mapping of homologs : NCBIJAK3 [Mapview]
OMIM600173   600802   
Gene and transcription
Genbank (Entrez)AK296383 AK304392 BC028068 BF512748 BM561964
RefSeq transcript (Entrez)NM_000215
RefSeq genomic (Entrez)AC_000151 NC_000019 NC_018930 NG_007273 NT_011295 NW_001838484 NW_004929414
Consensus coding sequences : CCDS (NCBI)JAK3
Cluster EST : UnigeneHs.515247 [ NCBI ]
CGAP (NCI)Hs.515247
Alternative Splicing : Fast-db (Paris)GSHG0015618
Alternative Splicing GalleryENSG00000105639
Gene ExpressionJAK3 [ NCBI-GEO ]     JAK3 [ SEEK ]   JAK3 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP52333 (Uniprot)
NextProtP52333  [Medical]
With graphics : InterProP52333
Splice isoforms : SwissVarP52333 (Swissvar)
Catalytic activity : Enzyme2.7.10.2 [ Enzyme-Expasy ]   2.7.10.22.7.10.2 [ IntEnz-EBI ]   2.7.10.2 [ BRENDA ]   2.7.10.2 [ KEGG ]   
Domaine pattern : Prosite (Expaxy)FERM_1 (PS00660)    FERM_2 (PS00661)    FERM_3 (PS50057)    PROTEIN_KINASE_ATP (PS00107)    PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_TYR (PS00109)    SH2 (PS50001)   
Domains : Interpro (EBI)Band_41_domain    FERM_domain    Kinase-like_dom    Prot_kinase_dom    Protein_kinase_ATP_BS    Ser-Thr/Tyr_kinase_cat_dom    SH2    Tyr_kinase_AS    Tyr_kinase_cat_dom    Tyr_kinase_non-rcpt_Jak/Tyk2    Tyr_kinase_non-rcpt_Jak3   
Related proteins : CluSTrP52333
Domain families : Pfam (Sanger)Pkinase_Tyr (PF07714)   
Domain families : Pfam (NCBI)pfam07714   
Domain families : Smart (EMBL)B41 (SM00295)  SH2 (SM00252)  TyrKc (SM00219)  
DMDM Disease mutations3718
Blocks (Seattle)P52333
PDB (SRS)1YVJ    3LXK    3LXL    3PJC    4HVD    4HVG    4HVH    4HVI   
PDB (PDBSum)1YVJ    3LXK    3LXL    3PJC    4HVD    4HVG    4HVH    4HVI   
PDB (IMB)1YVJ    3LXK    3LXL    3PJC    4HVD    4HVG    4HVH    4HVI   
PDB (RSDB)1YVJ    3LXK    3LXL    3PJC    4HVD    4HVG    4HVH    4HVI   
Human Protein AtlasENSG00000105639
Peptide AtlasP52333
HPRD02547
IPIIPI00002773   IPI00219418   IPI00910959   IPI00911092   
Protein Interaction databases
DIP (DOE-UCLA)P52333
IntAct (EBI)P52333
FunCoupENSG00000105639
BioGRIDJAK3
InParanoidP52333
Interologous Interaction database P52333
IntegromeDBJAK3
STRING (EMBL)JAK3
Ontologies - Pathways
Ontology : AmiGOnegative regulation of dendritic cell cytokine production  protein tyrosine kinase activity  protein tyrosine kinase activity  non-membrane spanning protein tyrosine kinase activity  protein binding  ATP binding  cytosol  cytoskeleton  protein phosphorylation  enzyme linked receptor protein signaling pathway  intracellular protein kinase cascade  tyrosine phosphorylation of STAT protein  STAT protein import into nucleus  endomembrane system  membrane  peptidyl-tyrosine phosphorylation  protein phosphatase binding  B cell differentiation  negative regulation of interleukin-10 production  negative regulation of interleukin-12 production  interleukin-4-mediated signaling pathway  T cell homeostasis  T cell homeostasis  innate immune response  negative regulation of FasL biosynthetic process  negative regulation of T-helper 1 cell differentiation  positive regulation of transcription from RNA polymerase II promoter  negative regulation of T cell activation  JAK-STAT cascade involved in growth hormone signaling pathway  regulation of T cell apoptotic process  negative regulation of thymocyte apoptotic process  response to interleukin-2  response to interleukin-4  response to interleukin-15  response to interleukin-9  
Ontology : EGO-EBInegative regulation of dendritic cell cytokine production  protein tyrosine kinase activity  protein tyrosine kinase activity  non-membrane spanning protein tyrosine kinase activity  protein binding  ATP binding  cytosol  cytoskeleton  protein phosphorylation  enzyme linked receptor protein signaling pathway  intracellular protein kinase cascade  tyrosine phosphorylation of STAT protein  STAT protein import into nucleus  endomembrane system  membrane  peptidyl-tyrosine phosphorylation  protein phosphatase binding  B cell differentiation  negative regulation of interleukin-10 production  negative regulation of interleukin-12 production  interleukin-4-mediated signaling pathway  T cell homeostasis  T cell homeostasis  innate immune response  negative regulation of FasL biosynthetic process  negative regulation of T-helper 1 cell differentiation  positive regulation of transcription from RNA polymerase II promoter  negative regulation of T cell activation  JAK-STAT cascade involved in growth hormone signaling pathway  regulation of T cell apoptotic process  negative regulation of thymocyte apoptotic process  response to interleukin-2  response to interleukin-4  response to interleukin-15  response to interleukin-9  
Pathways : BIOCARTAIL-7 Signal Transduction [Genes]    IL-2 Receptor Beta Chain in T cell Activation [Genes]    Stat3 Signaling Pathway [Genes]    IL 6 signaling pathway [Genes]    IL 2 signaling pathway [Genes]    IL 4 signaling pathway [Genes]    IL22 Soluble Receptor Signaling [Genes]   
Pathways : KEGGAdipocytokine signaling pathway    Jak-STAT signaling pathway   
REACTOMEJAK3
Protein Interaction DatabaseJAK3
Wikipedia pathwaysJAK3
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)JAK3
SNP (GeneSNP Utah)JAK3
SNP : HGBaseJAK3
Genetic variants : HAPMAPJAK3
1000_GenomesJAK3 
ICGC programENSG00000105639 
Cancer Gene: CensusJAK3 
Somatic Mutations in Cancer : COSMICJAK3 
CONAN: Copy Number AnalysisJAK3 
Mutations and Diseases : HGMDJAK3
OMIM600173    600802   
GENETestsJAK3
Disease Genetic AssociationJAK3
Huge Navigator JAK3 [HugePedia]  JAK3 [HugeCancerGEM]
Genomic VariantsJAK3  JAK3 [DGVbeta]
Exome VariantJAK3
dbVarJAK3
ClinVarJAK3
snp3D : Map Gene to Disease3718
General knowledge
Homologs : HomoloGeneJAK3
Homology/Alignments : Family Browser (UCSC)JAK3
Phylogenetic Trees/Animal Genes : TreeFamJAK3
Chemical/Protein Interactions : CTD3718
Chemical/Pharm GKB GenePA29990
Clinical trialJAK3
Cancer Resource (Charite)ENSG00000105639
Other databases
Probes
Litterature
PubMed169 Pubmed reference(s) in Entrez
CoreMineJAK3
iHOPJAK3

Bibliography

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Genomic sequence, organization, and chromosomal localization of human JAK3.
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The DNA sequence and biology of human chromosome 19.
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Activation of the Jak3 pathway and myeloid differentiation.
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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.
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PMID 17252020
 
A novel mutation of intron 22 in Janus kinase 3-deficient severe combined immunodeficiency.
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Contributor(s)

Written07-2007Ping Shi, Hesham M Amin
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA

Citation

This paper should be referenced as such :
Shi P, Amin HM . JAK3 (Janus Kinase 3 or Just Another Kinase 3). Atlas Genet Cytogenet Oncol Haematol. July 2007 .
URL : http://AtlasGeneticsOncology.org/Genes/JAK3ID41032ch19p13.html

The various updated versions of this paper are referenced and archived by INIST as such :
http://documents.irevues.inist.fr/bitstream/2042/38474/1/07-2007-JAK3ID41032ch19p13.pdf   [ Bibliographic record ]

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