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JAK1 (Janus kinase 1)

Written2009-09Laurent Knoops, Tekla Hornakova, Jean-Christophe Renauld
Hematology unit, Cliniques Universitaires Saint-Luc (LK); Ludwig Institute for Cancer Research de Duve Institute, Université Catholique de Louvain, Avenue Hippocrate 74, B-1200 Brussels, Belgium (LK, TH, JCR)

(Note : for Links provided by Atlas : click)

Identity

Alias_namesJAK1B
Alias_symbol (synonym)JAK1A
JTK3
HGNC (Hugo) JAK1
LocusID (NCBI) 3716
Atlas_Id 41031
Location 1p31.3  [Link to chromosome band 1p31]
Location_base_pair Starts at 65298906 and ends at 65432619 bp from pter ( according to hg19-Feb_2009)  [Mapping JAK1.png]
Fusion genes
(updated 2016)
JAK1 (1p31.3) / ATF3 (1q32.3)JAK1 (1p31.3) / HSD11B1 (1q32.2)JAK1 (1p31.3) / JAK1 (1p31.3)
NSRP1 (17q11.2) / JAK1 (1p31.3)PA2G4 (12q13.2) / JAK1 (1p31.3)PDE4B (1p31.3) / JAK1 (1p31.3)
SCARB2 (4q21.1) / JAK1 (1p31.3)SH3BGRL (Xq21.1) / JAK1 (1p31.3)SMOC1 (14q24.2) / JAK1 (1p31.3)

DNA/RNA

Description 25 exons spanning roughly 135 kb of genomic DNA.
Transcription 5053 bp pre-mRNA; 1 transcript described.

Protein

Description 1154 amino acids; 133,3 kDa; JAK1 contains a N-terminal FERM domain, responsible of the binding to the receptor, a central Src homology 2 (SH2) domain, and two C-terminal domains: a tyrosine kinase domain JH1 and a pseudokinase domain JH2.
Expression Ubiquitous.
Localisation Intracellular, associated to cytokine receptors.
Function JAK1 is a non-receptor tyrosine kinase that associates to cytokine receptors without intrinsic kinase activity to mediate cytokine-induced signal transduction; JAK1 associates with numerous cytokine receptors chains and is involved in signaling by the majority of cytokines: the gamma-C family (IL-2, IL-4, IL-7, IL-9, IL-15, IL-21), the gp130 family (IL-6, OSM, LIF, ...), interferons, ...
Homology JAK1 belongs to the janus kinase subfamily; four mammalian JAKs have been identified (JAK1, JAK2, JAK3 and TYK2); human JAK1 is > 90% identical to the mouse and the rat JAK1 homologs.

Implicated in

Note
Entity Acute lymphoblastic leukemia T cell type (T-ALL) and Acute lymphoblastic leukemia B cell type (B-ALL)
Prognosis JAK1 mutations are associated with advanced age, poor response to therapy and overall prognosis (Flex et al., 2008).
Oncogenesis Somatic JAK1 mutations occur in T cell acute lymphoblastic leukemia (ALL). These mutations seem to be more frequent among adult T-ALL patients, but the frequency varies between studies: 8/38 (21.0%; adult; Flex et al., 2008), 1/49 (2.0%; children; Flex et al., 2008), 2/11 (27.3%; adult; Jeong et al., 2008), 4/108 (3.7%; adult; Asnafi et al., 2009). These mutations represent gain of function mutations that participate in the leukemogenic process by inducing the constitutive activation of the JAK-STAT pathway.
Table 1: Somatic mutations in JAK1 found in T-ALL patients.
Amino acid substitutionProof of hyperactivitydomainreference
S512L SH2Flex et al., 2008
A634DYesPseudokinaseFlex et al., 2008
Y652H PseudokinaseAsnafi et al., 2009
V658FYesPseudokinaseJeong et al., 2008
R724HYesPseudokinaseFlex et al., 2008
R724Q PseudokinaseAsnafi et al., 2009
T782M PseudokinaseJeong et al., 2008
L783F PseudokinaseJeong et al., 2008
R879S KinaseFlex et al., 2008
R879CYesKinaseFlex et al., 2008
R879H KinaseeFlex et al., 2008

JAK1 mutations were found in 3 B-cell ALL samples after the resequencing of 173 B-ALL (Flex et al., 2008) and in 3 samples after the resequencing of 187 high risk childhood B-ALL (Mullighan et al., 2009). No mutations were found after the resequencing of 69 B-ALL (Jeong et al., 2008).
Table 2: Somatic mutations in JAK1 found in B-ALL patients.

Amino acid substitutionProof of hyperactivitydomainreference
K204M FERMFlex et al., 2008
L624_R629>WYesPseudokinaseMullighan et al., 2009
A634DYesPseudokinaseFlex et al., 2008
S646FYesPseudokinaseMullighan et al., 2009
L653F PseudokinaseFlex et al., 2008
V658FYesPseudokinaseMullighan et al., 2009
R724HYesPseudokinaseFlex et al., 2008

JAK1 mutants induce the activation of different cytokine-receptor complexes like the IL-9 receptor or the IL-2 receptor, that will induce the constitutive activation of the JAK-STAT pathway.

  
Entity Acute myeloid leukemia (AML)
Oncogenesis JAK1 mutations were found in two AML samples after the resequencing of 94 AML (Xiang et al., 2008) and in one AML sample after the resequencing of 105 AML.
Table 3: Somatic mutations in JAK1 found in AML samples.
Amino acid substitutionProof of hyperactivitydomainreference
T478S SH2Xiang et al., 2008
V623A PseudokinaseXiang et al., 2008
V658FYesPseudokinaseJeong et al., 2008

  
Entity Hepatocellular carcinoma
Oncogenesis JAK1 mutations were found in one hepatocellular carcinoma sample after the screening of 84 hepatocellular carcinoma.
Table 4: Somatic mutations in JAK1 found in hepatocellular carcinomas.
Amino acid substitutionProof of hyperactivitydomainreference
Q644H;V645F PseudokinaseXie et al., 2009

  
Entity Breast cancer
Oncogenesis JAK1 mutation was found in a breast cancer sample after the resequencing of 90 breast cancers.
Table 5: Somatic mutations in JAK1 found in breast cancer samples.
Amino acid substitutionProof of hyperactivitydomainreference
H647Y PseudokinaseJeong et al., 2008

  
Entity Non-small cell lung cancer
Oncogenesis JAK1 mutation was found in a non-small cell lung cancer sample after the resequencing of 47 non-small cell lung cancer samples.
Table 6: Somatic mutations in JAK1 found in non-small cell lung cancer samples.
Amino acid substitutionProof of hyperactivitydomainreference
P782M PseudokinaseJeong et al., 2008

  

Bibliography

JAK1 mutations are not frequent events in adult T-ALL: a GRAALL study.
Asnafi V, Le Noir S, Lhermitte L, Gardin C, Legrand F, Vallantin X, Malfuson JV, Ifrah N, Dombret H, Macintyre E.
Br J Haematol. 2009 Sep 18. [Epub ahead of print]
PMID 19764985
 
Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia.
Flex E, Petrangeli V, Stella L, Chiaretti S, Hornakova T, Knoops L, Ariola C, Fodale V, Clappier E, Paoloni F, Martinelli S, Fragale A, Sanchez M, Tavolaro S, Messina M, Cazzaniga G, Camera A, Pizzolo G, Tornesello A, Vignetti M, Battistini A, Cave H, Gelb BD, Renauld JC, Biondi A, Constantinescu SN, Foa R, Tartaglia M.
J Exp Med. 2008 Apr 14;205(4):751-8. Epub 2008 Mar 24.
PMID 18362173
 
Acute lymphoblastic leukemia-associated JAK1 mutants activate the Janus kinase/STAT pathway via interleukin-9 receptor alpha homodimers.
Hornakova T, Staerk J, Royer Y, Flex E, Tartaglia M, Constantinescu SN, Knoops L, Renauld JC.
J Biol Chem. 2009 Mar 13;284(11):6773-81. Epub 2009 Jan 12.
PMID 19139102
 
Somatic mutations of JAK1 and JAK3 in acute leukemias and solid cancers.
Jeong EG, Kim MS, Nam HK, Min CK, Lee S, Chung YJ, Yoo NJ, Lee SH.
Clin Cancer Res. 2008 Jun 15;14(12):3716-21.
PMID 18559588
 
JAK kinases overexpression promotes in vitro cell transformation.
Knoops L, Hornakova T, Royer Y, Constantinescu SN, Renauld JC.
Oncogene. 2008 Mar 6;27(11):1511-9. Epub 2007 Sep 17.
PMID 17873904
 
JAK mutations in high-risk childhood acute lymphoblastic leukemia.
Mullighan CG, Zhang J, Harvey RC, Collins-Underwood JR, Schulman BA, Phillips LA, Tasian SK, Loh ML, Su X, Liu W, Devidas M, Atlas SR, Chen IM, Clifford RJ, Gerhard DS, Carroll WL, Reaman GH, Smith M, Downing JR, Hunger SP, Willman CL.
Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9414-8. Epub 2009 May 22.
PMID 19470474
 
Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia.
Tomasson MH, Xiang Z, Walgren R, Zhao Y, Kasai Y, Miner T, Ries RE, Lubman O, Fremont DH, McLellan MD, Payton JE, Westervelt P, DiPersio JF, Link DC, Walter MJ, Graubert TA, Watson M, Baty J, Heath S, Shannon WD, Nagarajan R, Bloomfield CD, Mardis ER, Wilson RK, Ley TJ.
Blood. 2008 May 1;111(9):4797-808. Epub 2008 Feb 12.
PMID 18270328
 
Identification of somatic JAK1 mutations in patients with acute myeloid leukemia.
Xiang Z, Zhao Y, Mitaksov V, Fremont DH, Kasai Y, Molitoris A, Ries RE, Miner TL, McLellan MD, DiPersio JF, Link DC, Payton JE, Graubert TA, Watson M, Shannon W, Heath SE, Nagarajan R, Mardis ER, Wilson RK, Ley TJ, Tomasson MH.
Blood. 2008 May 1;111(9):4809-12. Epub 2007 Dec 26.
PMID 18160671
 
Mutational analysis of JAK1 gene in human hepatocellular carcinoma.
Xie HJ, Bae HJ, Noh JH, Eun JW, Kim JK, Jung KH, Ryu JC, Ahn YM, Kim SY, Lee SH, Yoo NJ, Lee JY, Park WS, Nam SW.
Neoplasma. 2009;56(2):136-40.
PMID 19239328
 

Citation

This paper should be referenced as such :
Knoops, L ; Hornakova, T ; Renauld, JC
JAK1 (Janus kinase 1)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(8):717-719.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/JAK1ID41031ch1p31.html


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  Anaplastic large cell lymphoma, ALK-negative


External links

Nomenclature
HGNC (Hugo)JAK1   6190
Cards
AtlasJAK1ID41031ch1p31
Entrez_Gene (NCBI)JAK1  3716  Janus kinase 1
AliasesJAK1A; JAK1B; JTK3
GeneCards (Weizmann)JAK1
Ensembl hg19 (Hinxton)ENSG00000162434 [Gene_View]  chr1:65298906-65432619 [Contig_View]  JAK1 [Vega]
Ensembl hg38 (Hinxton)ENSG00000162434 [Gene_View]  chr1:65298906-65432619 [Contig_View]  JAK1 [Vega]
ICGC DataPortalENSG00000162434
TCGA cBioPortalJAK1
AceView (NCBI)JAK1
Genatlas (Paris)JAK1
WikiGenes3716
SOURCE (Princeton)JAK1
Genetics Home Reference (NIH)JAK1
Genomic and cartography
GoldenPath hg19 (UCSC)JAK1  -     chr1:65298906-65432619 -  1p32.3-p31.3   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)JAK1  -     1p32.3-p31.3   [Description]    (hg38-Dec_2013)
EnsemblJAK1 - 1p32.3-p31.3 [CytoView hg19]  JAK1 - 1p32.3-p31.3 [CytoView hg38]
Mapping of homologs : NCBIJAK1 [Mapview hg19]  JAK1 [Mapview hg38]
OMIM147795   
Gene and transcription
Genbank (Entrez)AB209057 AB219242 AK128375 AK314257 BC009079
RefSeq transcript (Entrez)NM_001320923 NM_001321852 NM_001321853 NM_001321854 NM_001321855 NM_001321856 NM_001321857 NM_002227
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)JAK1
Cluster EST : UnigeneHs.207538 [ NCBI ]
CGAP (NCI)Hs.207538
Alternative Splicing GalleryENSG00000162434
Gene ExpressionJAK1 [ NCBI-GEO ]   JAK1 [ EBI - ARRAY_EXPRESS ]   JAK1 [ SEEK ]   JAK1 [ MEM ]
Gene Expression Viewer (FireBrowse)JAK1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)3716
GTEX Portal (Tissue expression)JAK1
Protein : pattern, domain, 3D structure
UniProt/SwissProtP23458   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP23458  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP23458
Splice isoforms : SwissVarP23458
PhosPhoSitePlusP23458
Domaine pattern : Prosite (Expaxy)FERM_3 (PS50057)    PROTEIN_KINASE_ATP (PS00107)    PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_TYR (PS00109)    SH2 (PS50001)   
Domains : Interpro (EBI)Band_41_domain    FERM_central    FERM_domain    Kinase-like_dom    PH_dom-like    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_Jak1   
Domain families : Pfam (Sanger)Pkinase_Tyr (PF07714)   
Domain families : Pfam (NCBI)pfam07714   
Domain families : Smart (EMBL)B41 (SM00295)  SH2 (SM00252)  TyrKc (SM00219)  
Conserved Domain (NCBI)JAK1
DMDM Disease mutations3716
Blocks (Seattle)JAK1
PDB (SRS)3EYG    3EYH    4E4L    4E4N    4E5W    4EHZ    4EI4    4FK6    4GS0    4I5C    4IVB    4IVC    4IVD    4K6Z    4K77    4L00    4L01    5E1E    5HX8    5IXD    5IXI   
PDB (PDBSum)3EYG    3EYH    4E4L    4E4N    4E5W    4EHZ    4EI4    4FK6    4GS0    4I5C    4IVB    4IVC    4IVD    4K6Z    4K77    4L00    4L01    5E1E    5HX8    5IXD    5IXI   
PDB (IMB)3EYG    3EYH    4E4L    4E4N    4E5W    4EHZ    4EI4    4FK6    4GS0    4I5C    4IVB    4IVC    4IVD    4K6Z    4K77    4L00    4L01    5E1E    5HX8    5IXD    5IXI   
PDB (RSDB)3EYG    3EYH    4E4L    4E4N    4E5W    4EHZ    4EI4    4FK6    4GS0    4I5C    4IVB    4IVC    4IVD    4K6Z    4K77    4L00    4L01    5E1E    5HX8    5IXD    5IXI   
Structural Biology KnowledgeBase3EYG    3EYH    4E4L    4E4N    4E5W    4EHZ    4EI4    4FK6    4GS0    4I5C    4IVB    4IVC    4IVD    4K6Z    4K77    4L00    4L01    5E1E    5HX8    5IXD    5IXI   
SCOP (Structural Classification of Proteins)3EYG    3EYH    4E4L    4E4N    4E5W    4EHZ    4EI4    4FK6    4GS0    4I5C    4IVB    4IVC    4IVD    4K6Z    4K77    4L00    4L01    5E1E    5HX8    5IXD    5IXI   
CATH (Classification of proteins structures)3EYG    3EYH    4E4L    4E4N    4E5W    4EHZ    4EI4    4FK6    4GS0    4I5C    4IVB    4IVC    4IVD    4K6Z    4K77    4L00    4L01    5E1E    5HX8    5IXD    5IXI   
SuperfamilyP23458
Human Protein AtlasENSG00000162434
Peptide AtlasP23458
HPRD00992
IPIIPI00784013   
Protein Interaction databases
DIP (DOE-UCLA)P23458
IntAct (EBI)P23458
FunCoupENSG00000162434
BioGRIDJAK1
STRING (EMBL)JAK1
ZODIACJAK1
Ontologies - Pathways
QuickGOP23458
Ontology : AmiGOMAPK cascade  protein tyrosine kinase activity  protein tyrosine kinase activity  non-membrane spanning protein tyrosine kinase activity  non-membrane spanning protein tyrosine kinase activity  Ras guanyl-nucleotide exchange factor activity  receptor binding  growth hormone receptor binding  protein binding  ATP binding  nucleus  cytoplasm  cytosol  cytoskeleton  focal adhesion  protein phosphorylation  transmembrane receptor protein tyrosine kinase signaling pathway  endomembrane system  cell migration  protein phosphatase binding  cell differentiation  extrinsic component of cytoplasmic side of plasma membrane  ubiquitin protein ligase binding  CCR5 chemokine receptor binding  intracellular signal transduction  peptidyl-tyrosine autophosphorylation  interleukin-2-mediated signaling pathway  regulation of cell proliferation  positive regulation of GTPase activity  innate immune response  response to antibiotic  metal ion binding  interferon-gamma-mediated signaling pathway  regulation of interferon-gamma-mediated signaling pathway  type I interferon signaling pathway  regulation of type I interferon-mediated signaling pathway  positive regulation of sprouting angiogenesis  
Ontology : EGO-EBIMAPK cascade  protein tyrosine kinase activity  protein tyrosine kinase activity  non-membrane spanning protein tyrosine kinase activity  non-membrane spanning protein tyrosine kinase activity  Ras guanyl-nucleotide exchange factor activity  receptor binding  growth hormone receptor binding  protein binding  ATP binding  nucleus  cytoplasm  cytosol  cytoskeleton  focal adhesion  protein phosphorylation  transmembrane receptor protein tyrosine kinase signaling pathway  endomembrane system  cell migration  protein phosphatase binding  cell differentiation  extrinsic component of cytoplasmic side of plasma membrane  ubiquitin protein ligase binding  CCR5 chemokine receptor binding  intracellular signal transduction  peptidyl-tyrosine autophosphorylation  interleukin-2-mediated signaling pathway  regulation of cell proliferation  positive regulation of GTPase activity  innate immune response  response to antibiotic  metal ion binding  interferon-gamma-mediated signaling pathway  regulation of interferon-gamma-mediated signaling pathway  type I interferon signaling pathway  regulation of type I interferon-mediated signaling pathway  positive regulation of sprouting angiogenesis  
Pathways : BIOCARTAIL22 Soluble Receptor Signaling [Genes]    IL-2 Receptor Beta Chain in T cell Activation [Genes]    IL 4 signaling pathway [Genes]    Stat3 Signaling Pathway [Genes]    EGF Signaling Pathway [Genes]    IFN alpha signaling pathway [Genes]    IL-7 Signal Transduction [Genes]    IL 6 signaling pathway [Genes]    IL 2 signaling pathway [Genes]    IFN gamma signaling pathway [Genes]    PDGF Signaling Pathway [Genes]    IL-10 Anti-inflammatory Signaling Pathway [Genes]   
Pathways : KEGGPI3K-Akt signaling pathway    Osteoclast differentiation    Jak-STAT signaling pathway    Leishmaniasis    Toxoplasmosis    Tuberculosis    Hepatitis C    Hepatitis B    Measles    Influenza A    HTLV-I infection    Herpes simplex infection    Epstein-Barr virus infection    Pathways in cancer    Viral carcinogenesis    Pancreatic cancer   
REACTOMEP23458 [protein]
REACTOME PathwaysR-HSA-912694 [pathway]
NDEx NetworkJAK1
Atlas of Cancer Signalling NetworkJAK1
Wikipedia pathwaysJAK1
Orthology - Evolution
OrthoDB3716
GeneTree (enSembl)ENSG00000162434
Phylogenetic Trees/Animal Genes : TreeFamJAK1
HOVERGENP23458
HOGENOMP23458
Homologs : HomoloGeneJAK1
Homology/Alignments : Family Browser (UCSC)JAK1
Gene fusions - Rearrangements
Fusion : MitelmanJAK1/HSD11B1 [1p31.3/1q32.2]  
Fusion : MitelmanPDE4B/JAK1 [1p31.3/1p31.3]  [t(1;1)(p31;p31)]  
Fusion: TCGAJAK1 1p31.3 HSD11B1 1q32.2 OV
Fusion: TCGAPDE4B 1p31.3 JAK1 1p31.3 BRCA
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerJAK1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)JAK1
dbVarJAK1
ClinVarJAK1
1000_GenomesJAK1 
Exome Variant ServerJAK1
ExAC (Exome Aggregation Consortium)JAK1 (select the gene name)
Genetic variants : HAPMAP3716
Genomic Variants (DGV)JAK1 [DGVbeta]
DECIPHER (Syndromes)1:65298906-65432619  ENSG00000162434
CONAN: Copy Number AnalysisJAK1 
Mutations
ICGC Data PortalJAK1 
TCGA Data PortalJAK1 
Broad Tumor PortalJAK1
OASIS PortalJAK1 [ Somatic mutations - Copy number]
Cancer Gene: CensusJAK1 
Somatic Mutations in Cancer : COSMICJAK1  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDJAK1
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch JAK1
DgiDB (Drug Gene Interaction Database)JAK1
DoCM (Curated mutations)JAK1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)JAK1 (select a term)
intoGenJAK1
NCG5 (London)JAK1
Cancer3DJAK1(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM147795   
Orphanet
MedgenJAK1
Genetic Testing Registry JAK1
NextProtP23458 [Medical]
TSGene3716
GENETestsJAK1
Huge Navigator JAK1 [HugePedia]
snp3D : Map Gene to Disease3716
BioCentury BCIQJAK1
ClinGenJAK1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD3716
Chemical/Pharm GKB GenePA29988
Clinical trialJAK1
Miscellaneous
canSAR (ICR)JAK1 (select the gene name)
Probes
Litterature
PubMed308 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineJAK1
EVEXJAK1
GoPubMedJAK1
iHOPJAK1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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