JAK1 (Janus kinase 1)

2009-09-01   Laurent 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)

Identity

HGNC
LOCATION
1p31.3
LOCUSID
ALIAS
AIIDE,JAK1A,JAK1B,JTK3
FUSION GENES

DNA/RNA

Description

25 exons spanning roughly 135 kb of genomic DNA.

Transcription

5053 bp pre-mRNA; 1 transcript described.

Proteins

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

Entity name
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.
Amino acid substitutionProof of hyperactivitydomainreference
R724HYesPseudokinaseFlex et al., 2008
V658FYesPseudokinaseMullighan et al., 2009

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).
L624_R629>WYesPseudokinaseMullighan et al., 2009 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 name
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.
Amino acid substitutionProof of hyperactivitydomainreference
V623A PseudokinaseXiang et al., 2008
V658FYesPseudokinaseJeong et al., 2008

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

Entity name
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 name
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

Pubmed IDLast YearTitleAuthors
197649852010JAK1 mutations are not frequent events in adult T-ALL: a GRAALL study.Asnafi V et al
183621732008Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia.Flex E et al
191391022009Acute lymphoblastic leukemia-associated JAK1 mutants activate the Janus kinase/STAT pathway via interleukin-9 receptor alpha homodimers.Hornakova T et al
185595882008Somatic mutations of JAK1 and JAK3 in acute leukemias and solid cancers.Jeong EG et al
178739042008JAK kinases overexpression promotes in vitro cell transformation.Knoops L et al
194704742009JAK mutations in high-risk childhood acute lymphoblastic leukemia.Mullighan CG et al
182703282008Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia.Tomasson MH et al
181606712008Identification of somatic JAK1 mutations in patients with acute myeloid leukemia.Xiang Z et al
192393282009Mutational analysis of JAK1 gene in human hepatocellular carcinoma.Xie HJ et al

Other Information

Locus ID:

NCBI: 3716
MIM: 147795
HGNC: 6190
Ensembl: ENSG00000162434

Variants:

dbSNP: 3716
ClinVar: 3716
TCGA: ENSG00000162434
COSMIC: JAK1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000162434ENST00000342505P23458

Expression (GTEx)

0
50
100
150

Pathways

PathwaySourceExternal ID
Jak-STAT signaling pathwayKEGGko04630
Pancreatic cancerKEGGko05212
Jak-STAT signaling pathwayKEGGhsa04630
Pathways in cancerKEGGhsa05200
Pancreatic cancerKEGGhsa05212
NOD-like receptor signaling pathwayKEGGko04621
NOD-like receptor signaling pathwayKEGGhsa04621
LeishmaniasisKEGGko05140
LeishmaniasisKEGGhsa05140
ToxoplasmosisKEGGko05145
ToxoplasmosisKEGGhsa05145
Hepatitis CKEGGko05160
Hepatitis CKEGGhsa05160
Osteoclast differentiationKEGGko04380
Osteoclast differentiationKEGGhsa04380
MeaslesKEGGko05162
MeaslesKEGGhsa05162
TuberculosisKEGGko05152
TuberculosisKEGGhsa05152
Influenza AKEGGko05164
Influenza AKEGGhsa05164
HTLV-I infectionKEGGko05166
HTLV-I infectionKEGGhsa05166
Herpes simplex infectionKEGGko05168
Herpes simplex infectionKEGGhsa05168
Epstein-Barr virus infectionKEGGhsa05169
Epstein-Barr virus infectionKEGGko05169
Viral carcinogenesisKEGGhsa05203
Viral carcinogenesisKEGGko05203
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
Hepatitis BKEGGhsa05161
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
Interferon SignalingREACTOMER-HSA-913531
Interferon alpha/beta signalingREACTOMER-HSA-909733
Regulation of IFNA signalingREACTOMER-HSA-912694
Interferon gamma signalingREACTOMER-HSA-877300
Regulation of IFNG signalingREACTOMER-HSA-877312
Antiviral mechanism by IFN-stimulated genesREACTOMER-HSA-1169410
ISG15 antiviral mechanismREACTOMER-HSA-1169408
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-6 signalingREACTOMER-HSA-1059683
Interleukin-7 signalingREACTOMER-HSA-1266695
HemostasisREACTOMER-HSA-109582
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
VEGFA-VEGFR2 PathwayREACTOMER-HSA-4420097
VEGFR2 mediated cell proliferationREACTOMER-HSA-5218921
Signaling by SCF-KITREACTOMER-HSA-1433557
MAPK family signaling cascadesREACTOMER-HSA-5683057
MAPK1/MAPK3 signalingREACTOMER-HSA-5684996
RAF-independent MAPK1/3 activationREACTOMER-HSA-112409
MAPK3 (ERK1) activationREACTOMER-HSA-110056
MAPK1 (ERK2) activationREACTOMER-HSA-112411
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
Interleukin-6 family signalingREACTOMER-HSA-6783589
IL-6-type cytokine receptor ligand interactionsREACTOMER-HSA-6788467
EGFR tyrosine kinase inhibitor resistanceKEGGko01521
EGFR tyrosine kinase inhibitor resistanceKEGGhsa01521
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
Interleukin-10 signalingREACTOMER-HSA-6783783

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA27844ERBB2GenePathwayassociated
PA27846ERBB3GenePathwayassociated
PA27847ERBB4GenePathwayassociated
PA337STAT3GenePathwayassociated
PA338STAT5AGenePathwayassociated
PA36183STAT1GenePathwayassociated
PA36184STAT2GenePathwayassociated
PA36185STAT4GenePathwayassociated
PA36186STAT5BGenePathwayassociated
PA7360EGFRGenePathwayassociated

References

Pubmed IDYearTitleCitations
279035002017Primary Resistance to PD-1 Blockade Mediated by JAK1/2 Mutations.241
294052012018Targeting the IL-6/JAK/STAT3 signalling axis in cancer.206
194704742009JAK mutations in high-risk childhood acute lymphoblastic leukemia.195
201390932010Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia.150
218404872011ROCK and JAK1 signaling cooperate to control actomyosin contractility in tumor cells and stroma.124
183621732008Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia.117
183621732008Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia.117
183200732008Inhibition of JAK1, 2/STAT3 signaling induces apoptosis, cell cycle arrest, and reduces tumor cell invasion in colorectal cancer cells.114
190177632009Enhanced expression of Janus kinase-signal transducer and activator of transcription pathway members in human diabetic nephropathy.107
177034122007Genetic susceptibility to respiratory syncytial virus bronchiolitis is predominantly associated with innate immune genes.100

Citation

Laurent Knoops ; Tekla Hornakova ; Jean-Christophe Renauld

JAK1 (Janus kinase 1)

Atlas Genet Cytogenet Oncol Haematol. 2009-09-01

Online version: http://atlasgeneticsoncology.org/gene/41031/jak1id41031ch1p31