Reviewed, UniProtKB/Swiss-Prot O60674 (JAK2_HUMAN)

Names and origin

Protein names

Recommended name:
    Tyrosine-protein kinase JAK2
    EC=2.7.10.2
Alternative name(s):
    Janus kinase 2
      Short name=JAK-2

Gene names

Name:

JAK2

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	1132 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Plays a role in leptin signaling and control of body weight By similarity. Tyrosine kinase of the non-receptor type, involved in interleukin-3 and probably interleukin-23 signal transduction.
Catalytic activity	ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Subunit structure	Interacts with SIRPA and SH2B1 By similarity. Interacts with IL23R, SKB1 and STAM2.
Subcellular location	Intracytoplasmic membrane; Peripheral membrane proteinBy similarity. Note= Wholly intracellular, possibly membrane associated By similarity.
Tissue specificity	Expressed in blood, bone marrow and lymph node.
Domain	Possesses two phosphotransferase domains. The second one probably contains the catalytic domain By similarity, while the presence of slight differences suggest a different role for domain 1.
Post-translational modification	Leptin promotes phosphorylation on tyrosine residues, including phosphorylation on Tyr-813 By similarity.
Involvement in disease	Chromosomal aberrations involving JAK2 are found in both chronic and acute forms of eosinophilic, lymphoblastic and myeloid leukemia. Translocation t(8;9)(p22;p24) with PCM1 links the protein kinase domain of JAK2 to the major portion of PCM1. Translocation t(9;12)(p24;p13) with ETV6. Defects in JAK2 are a cause of susceptibility to Budd-Chiari syndrome [MIM:600880]. Budd-Chiari syndrome is a spectrum of disease states, including anatomic abnormalities and hypercoagulable disorders, resulting in hepatic venous outflow occlusion. Clinical manifestations observed in the majority of patients include hepatomegaly, right upper quadrant pain, and abdominal ascites. Defects in JAK2 are associated with polycythemia vera (PV) [MIM:263300]. PV, the most common form of primary polycythemia, is caused by somatic mutation in a single hematopoietic stem cell leading to clonal hematopoiesis. PV is a myeloproliferative disorder characterized predominantly by erythroid hyperplasia, but also by myeloid leukocytosis, thrombocytosis, and splenomegaly. Familial cases of PV are very rare and usually manifest in elderly patients. Defects in JAK2 gene may be a cause of essential thrombocythemia (ET) [MIM:187950]. ET is characterized by elevated platelet levels due to sustained proliferation of megakaryocytes, and frequently lead to thrombotic and haemorrhagic complications. Defects in JAK2 are associated with familial myelofibrosis [MIM:254450]. Myelofibrosis with myeloid metaplasia is a myeloproliferative disease with annual incidence of 0.5-1.5 cases per 100,000 individuals and age at diagnosis around 60 (an increased prevalence is noted in Ashkenazi Jews). Clinical manifestations depend on the type of blood cell affected and may include anemia, pallor, splenomegaly, hypermetabolic state, petechiae, ecchymosis, bleeding, lymphadenopathy, hepatomegaly, portal hypertension. Defects in JAK2 are a cause of acute myelogenous leukemia (AML) [MIM:601626]. AML is a malignant disease in which hematopoietic precursors are arrested in an early stage of development.
Sequence similarities	Belongs to the protein kinase superfamily. Tyr protein kinase family. JAK subfamily. Contains 1 FERM domain. Contains 1 protein kinase domain. Contains 1 SH2 domain.

Ontologies

Keywords
Cellular component	Membrane
Coding sequence diversity	Chromosomal rearrangement Polymorphism
Disease	Disease mutation Proto-oncogene
Domain	Repeat SH2 domain
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Transferase Tyrosine-protein kinase
PTM	Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	cell motion Traceable author statement. Source: ProtInc mesoderm development Traceable author statement. Source: ProtInc
Cellular component	cytoskeleton Inferred from electronic annotation. Source: InterPro endomembrane system Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	ATP binding Inferred from electronic annotation. Source: InterPro Janus kinase activity Inferred from electronic annotation. Source: InterPro SH2 domain binding Inferred from physical interaction. Source: UniProtKB non-membrane spanning protein tyrosine kinase activity Inferred from electronic annotation. Source: EC receptor binding Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
GRB2	P62993	1	EBI-518647,EBI-401755
NCK1	P16333	1	EBI-518647,EBI-389883
PIK3R1	P27986	1	EBI-518647,EBI-79464
PLCG1	P19174	1	EBI-518647,EBI-79387

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 1132

1132

Tyrosine-protein kinase JAK2

PRO_0000088112

Regions

Domain

37 – 380

344

FERM

Domain

401 – 482

82

SH2; atypical

Domain

545 – 809

265

Protein kinase 1

Domain

849 – 1124

276

Protein kinase 2

Nucleotide binding

855 – 863

9

ATP By similarity

Sites

Active site

976

1

Proton acceptor By similarity

Binding site

882

1

ATP By similarity

Site

352 – 353

2

Breakpoint for translocation to form PCM1-JAK2 fusion protein

Site

442 – 443

2

Breakpoint for translocation to form PCM1-JAK2 fusion protein

Site

450 – 451

2

Breakpoint for translocation to form PCM1-JAK2 fusion protein

Site

504 – 505

2

Breakpoint for translocation to form PCM1-JAK2 fusion protein

Site

710 – 711

2

Breakpoint for translocation to form PCM1-JAK2 fusion protein

Amino acid modifications

Modified residue

570

1

Phosphotyrosine By similarity

Modified residue

813

1

Phosphotyrosine By similarity

Modified residue

1007

1

Phosphotyrosine; by autocatalysis

Modified residue

1008

1

Phosphotyrosine

Natural variations

Natural variant

127

1

G → D

VAR_041716

Natural variant

191

1

K → Q in an ovarian serous carcinoma sample; somatic mutation.

VAR_041717

Natural variant

346

1

K → R

VAR_041718

Natural variant

377

1

A → E

VAR_041719

Natural variant

393

1

L → V: dbSNP rs35844880.

VAR_041720

Natural variant

537 – 539

3

FHK → L in myeloproliferative disorder with erythrocytosis.

VAR_032693

Natural variant

538 – 539

2

HK → QL in myeloproliferative disorder with erythrocytosis.

VAR_032694

Natural variant

539

1

K → L in myeloproliferative disorder with erythrocytosis; requires 2 nucleotide substitutions.

VAR_032695

Natural variant

584

1

D → E: dbSNP rs17490221.

VAR_043129

Natural variant

607

1

K → N in AML.

VAR_032696

Natural variant

617

1

V → F in PV and AML; associated with susceptibility to Budd-Chiari syndrome; somatic mutation in a high percentage of patients with essential thrombocythemia or myelofibrosis; leads to constitutive tyrosine phosphorylation activity that promotes cytokine hypersensitivity.

VAR_032697

Natural variant

1063

1

R → H: dbSNP rs41316003.

VAR_041721

Experimental info

Sequence conflict

321

1

P → S in AAC23982. Ref.1

Sequence conflict

1126

1

I → V in AAC23653. Ref.2

Secondary structure

1

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1132

Helix Strand Turn

Details...

Helix

846 – 848

3

Beta strand

849 – 858

10

Beta strand

861 – 868

8

Beta strand

872 – 874

3

Beta strand

878 – 886

9

Helix

889 – 903

15

Beta strand

913 – 917

5

Beta strand

926 – 930

5

Helix

937 – 943

7

Turn

945 – 947

3

Helix

950 – 969

20

Helix

979 – 981

3

Beta strand

982 – 986

5

Beta strand

989 – 992

4

Helix

1018 – 1020

3

Helix

1023 – 1027

5

Helix

1033 – 1048

16

Turn

1049 – 1051

3

Helix

1053 – 1055

3

Helix

1057 – 1065

9

Helix

1073 – 1083

11

Helix

1096 – 1105

10

Helix

1110 – 1112

3

Helix

1116 – 1131

16

Sequences

	Sequence		Length	Mass (Da)
	O60674-1 [UniParc]. Last modified January 24, 2001. Version 2. Checksum: C30669EF1A7DA80C	FASTA	1,132	130,674
	10 20 30 40 50 60 MGMACLTMTE MEGTSTSSIY QNGDISGNAN SMKQIDPVLQ VYLYHSLGKS EADYLTFPSG 70 80 90 100 110 120 EYVAEEICIA ASKACGITPV YHNMFALMSE TERIWYPPNH VFHIDESTRH NVLYRIRFYF 130 140 150 160 170 180 PRWYCSGSNR AYRHGISRGA EAPLLDDFVM SYLFAQWRHD FVHGWIKVPV THETQEECLG 190 200 210 220 230 240 MAVLDMMRIA KENDQTPLAI YNSISYKTFL PKCIRAKIQD YHILTRKRIR YRFRRFIQQF 250 260 270 280 290 300 SQCKATARNL KLKYLINLET LQSAFYTEKF EVKEPGSGPS GEEIFATIII TGNGGIQWSR 310 320 330 340 350 360 GKHKESETLT EQDLQLYCDF PNIIDVSIKQ ANQEGSNESR VVTIHKQDGK NLEIELSSLR 370 380 390 400 410 420 EALSFVSLID GYYRLTADAH HYLCKEVAPP AVLENIQSNC HGPISMDFAI SKLKKAGNQT 430 440 450 460 470 480 GLYVLRCSPK DFNKYFLTFA VERENVIEYK HCLITKNENE EYNLSGTKKN FSSLKDLLNC 490 500 510 520 530 540 YQMETVRSDN IIFQFTKCCP PKPKDKSNLL VFRTNGVSDV PTSPTLQRPT HMNQMVFHKI 550 560 570 580 590 600 RNEDLIFNES LGQGTFTKIF KGVRREVGDY GQLHETEVLL KVLDKAHRNY SESFFEAASM 610 620 630 640 650 660 MSKLSHKHLV LNYGVCVCGD ENILVQEFVK FGSLDTYLKK NKNCINILWK LEVAKQLAWA 670 680 690 700 710 720 MHFLEENTLI HGNVCAKNIL LIREEDRKTG NPPFIKLSDP GISITVLPKD ILQERIPWVP 730 740 750 760 770 780 PECIENPKNL NLATDKWSFG TTLWEICSGG DKPLSALDSQ RKLQFYEDRH QLPAPKWAEL 790 800 810 820 830 840 ANLINNCMDY EPDFRPSFRA IIRDLNSLFT PDYELLTEND MLPNMRIGAL GFSGAFEDRD 850 860 870 880 890 900 PTQFEERHLK FLQQLGKGNF GSVEMCRYDP LQDNTGEVVA VKKLQHSTEE HLRDFEREIE 910 920 930 940 950 960 ILKSLQHDNI VKYKGVCYSA GRRNLKLIME YLPYGSLRDY LQKHKERIDH IKLLQYTSQI 970 980 990 1000 1010 1020 CKGMEYLGTK RYIHRDLATR NILVENENRV KIGDFGLTKV LPQDKEYYKV KEPGESPIFW 1030 1040 1050 1060 1070 1080 YAPESLTESK FSVASDVWSF GVVLYELFTY IEKSKSPPAE FMRMIGNDKQ GQMIVFHLIE 1090 1100 1110 1120 1130 LLKNNGRLPR PDGCPDEIYM IMTECWNNNV NQRPSFRDLA LRVDQIRDNM AG

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning and characterization of human Jak-2 kinase: high mRNA expression in immune cells and muscle tissue." Saltzman A., Stone M., Franks C., Searfoss G., Munro R., Jaye M., Ivashchenko Y. Biochem. Biophys. Res. Commun. 246:627-633(1998) [PubMed: 9618263] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Cloning and characterization of the human homolog of mouse Jak2." Dalal I., Arpaia E., Dadi H., Kulkarni S., Squire J., Roifman C.M. Blood 91:844-851(1998) [PubMed: 9446644] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"Fusion of TEL, the ETS-variant gene 6 (ETV6), to the receptor-associated kinase JAK2 as a result of t(9;12) in a lymphoid and t(9;15;12) in a myeloid leukemia." Peeters P., Raynaud S.D., Cools J., Wlodarska I., Grosgeorge J., Philip P., Monpoux F., Van Rompaey L., Baens M., Van Den Berghe H., Marynen P. Blood 90:2535-2540(1997) [PubMed: 9326218] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], CHROMOSOMAL TRANSLOCATION WITH ETV6.
[4]	"DNA sequence and analysis of human chromosome 9." Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S., Bagguley C.L. , Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A., Frankland J.A., French L., Fricker D.G., Garner P., Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S., Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E., Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D., Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E., Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K., Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M., Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J., Dunham I. Nature 429:369-374(2004) [PubMed: 15164053] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"The human homologue of the yeast proteins Skb1 and Hsl7p interacts with Jak kinases and contains protein methyltransferase activity." Pollack B.P., Kotenko S.V., He W., Izotova L.S., Barnoski B.L., Pestka S. J. Biol. Chem. 274:31531-31542(1999) [PubMed: 10531356] [Abstract] Cited for: INTERACTION WITH SKB1.
[6]