JAK2_PONAB
ID JAK2_PONAB Reviewed; 1132 AA.
AC Q5RB23;
DT 18-MAR-2008, integrated into UniProtKB/Swiss-Prot.
DT 21-DEC-2004, sequence version 1.
DT 03-AUG-2022, entry version 123.
DE RecName: Full=Tyrosine-protein kinase JAK2 {ECO:0000250|UniProtKB:O60674};
DE EC=2.7.10.2 {ECO:0000250|UniProtKB:O60674};
DE AltName: Full=Janus kinase 2;
DE Short=JAK-2;
GN Name=JAK2 {ECO:0000250|UniProtKB:O60674};
OS Pongo abelii (Sumatran orangutan) (Pongo pygmaeus abelii).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Pongo.
OX NCBI_TaxID=9601;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Kidney;
RG The German cDNA consortium;
RL Submitted (NOV-2004) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Non-receptor tyrosine kinase involved in various processes
CC such as cell growth, development, differentiation or histone
CC modifications. Mediates essential signaling events in both innate and
CC adaptive immunity. In the cytoplasm, plays a pivotal role in signal
CC transduction via its association with type I receptors such as growth
CC hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR),
CC thrombopoietin (THPO); or type II receptors including IFN-alpha, IFN-
CC beta, IFN-gamma and multiple interleukins. Following ligand-binding to
CC cell surface receptors, phosphorylates specific tyrosine residues on
CC the cytoplasmic tails of the receptor, creating docking sites for STATs
CC proteins. Subsequently, phosphorylates the STATs proteins once they are
CC recruited to the receptor. Phosphorylated STATs then form homodimer or
CC heterodimers and translocate to the nucleus to activate gene
CC transcription. For example, cell stimulation with erythropoietin (EPO)
CC during erythropoiesis leads to JAK2 autophosphorylation, activation,
CC and its association with erythropoietin receptor (EPOR) that becomes
CC phosphorylated in its cytoplasmic domain. Then, STAT5 (STAT5A or
CC STAT5B) is recruited, phosphorylated and activated by JAK2. Once
CC activated, dimerized STAT5 translocates into the nucleus and promotes
CC the transcription of several essential genes involved in the modulation
CC of erythropoiesis. Part of a signaling cascade that is activated by
CC increased cellular retinol and that leads to the activation of STAT5
CC (STAT5A or STAT5B). In addition, JAK2 mediates angiotensin-2-induced
CC ARHGEF1 phosphorylation. Plays a role in cell cycle by phosphorylating
CC CDKN1B. Cooperates with TEC through reciprocal phosphorylation to
CC mediate cytokine-driven activation of FOS transcription. In the
CC nucleus, plays a key role in chromatin by specifically mediating
CC phosphorylation of 'Tyr-41' of histone H3 (H3Y41ph), a specific tag
CC that promotes exclusion of CBX5 (HP1 alpha) from chromatin.
CC {ECO:0000250|UniProtKB:O60674}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.2;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10028};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000305};
CC Note=Mn(2+) was used in the in vitro kinase assay but Mg(2+) is likely
CC to be the in vivo cofactor. {ECO:0000305};
CC -!- ACTIVITY REGULATION: Regulated by autophosphorylation, can both
CC activate or decrease activity. Heme regulates its activity by enhancing
CC the phosphorylation on Tyr-1007 and Tyr-1008.
CC {ECO:0000250|UniProtKB:O60674, ECO:0000250|UniProtKB:Q62120}.
CC -!- SUBUNIT: Interacts with IL23R, SKB1 and STAM2 (By similarity).
CC Interacts with EPOR. Interacts with LYN. Interacts with SIRPA.
CC Interacts with SH2B1. Interacts with TEC (By similarity). Interacts
CC with IFNGR2 (via intracellular domain) (By similarity). Interacts with
CC LEPR (Isoform B) (By similarity). Interacts with HSP90AB1; promotes
CC functional activation in a heat shock-dependent manner. Interacts with
CC STRA6 (By similarity). Interacts with RHEX; this interaction occurs in
CC a erythropoietin (EPO)-dependent manner (By similarity). Interacts with
CC ASB2; the interaction targets JAK2 for Notch-induced proteasomal
CC degradation (By similarity). {ECO:0000250|UniProtKB:O60674,
CC ECO:0000250|UniProtKB:Q62120}.
CC -!- SUBCELLULAR LOCATION: Endomembrane system {ECO:0000250}; Peripheral
CC membrane protein {ECO:0000250}. Cytoplasm {ECO:0000250}. Nucleus
CC {ECO:0000250}.
CC -!- DOMAIN: The N-terminal domain of JAKs mediates their interaction with
CC cytokine/interferon/growth hormone receptors. Possesses 2 protein
CC kinase domains. The second one probably contains the catalytic domain,
CC while the presence of slight differences suggest a different role for
CC protein kinase 1 (By similarity). {ECO:0000250}.
CC -!- PTM: Autophosphorylated, leading to regulate its activity. Leptin
CC promotes phosphorylation on tyrosine residues, including
CC phosphorylation on Tyr-813. Autophosphorylation on Tyr-119 in response
CC to EPO down-regulates its kinase activity. Autophosphorylation on Tyr-
CC 868, Tyr-966 and Tyr-972 in response to growth hormone (GH) are
CC required for maximal kinase activity. Also phosphorylated by TEC (By
CC similarity). Phosphorylated on tyrosine residues in response to
CC interferon gamma signaling. Phosphorylated on tyrosine residues in
CC response to a signaling cascade that is activated by increased cellular
CC retinol (By similarity). {ECO:0000250|UniProtKB:O60674,
CC ECO:0000250|UniProtKB:Q62120}.
CC -!- PTM: Undergoes Notch-induced ubiquitination and subsequent proteasomal
CC degradation which is mediated by ASB1 or ASB2, the substrate-
CC recognition components of probable ECS E3 ubiquitin-protein ligase
CC complexes. {ECO:0000250|UniProtKB:O60674}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. JAK subfamily. {ECO:0000255|PROSITE-ProRule:PRU00159}.
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DR EMBL; CR858835; CAH91037.1; -; mRNA.
DR RefSeq; NP_001125600.1; NM_001132128.1.
DR AlphaFoldDB; Q5RB23; -.
DR SMR; Q5RB23; -.
DR STRING; 9601.ENSPPYP00000021551; -.
DR GeneID; 100172517; -.
DR KEGG; pon:100172517; -.
DR CTD; 3717; -.
DR eggNOG; KOG0197; Eukaryota.
DR InParanoid; Q5RB23; -.
DR Proteomes; UP000001595; Unplaced.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005856; C:cytoskeleton; IEA:InterPro.
DR GO; GO:0012505; C:endomembrane system; IEA:UniProtKB-SubCell.
DR GO; GO:0016020; C:membrane; IEA:UniProtKB-KW.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0020037; F:heme binding; ISS:UniProtKB.
DR GO; GO:0042393; F:histone binding; ISS:UniProtKB.
DR GO; GO:0035401; F:histone kinase activity (H3-Y41 specific); ISS:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004713; F:protein tyrosine kinase activity; ISS:UniProtKB.
DR GO; GO:0042976; P:activation of Janus kinase activity; ISS:UniProtKB.
DR GO; GO:0002250; P:adaptive immune response; IEA:UniProtKB-KW.
DR GO; GO:0006325; P:chromatin organization; IEA:UniProtKB-KW.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; ISS:UniProtKB.
DR GO; GO:0030218; P:erythrocyte differentiation; ISS:UniProtKB.
DR GO; GO:0060397; P:growth hormone receptor signaling pathway via JAK-STAT; ISS:UniProtKB.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0035556; P:intracellular signal transduction; IEA:InterPro.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IEA:UniProt.
DR GO; GO:0042531; P:positive regulation of tyrosine phosphorylation of STAT protein; ISS:UniProtKB.
DR GO; GO:0043687; P:post-translational protein modification; ISS:UniProtKB.
DR GO; GO:0046777; P:protein autophosphorylation; ISS:UniProtKB.
DR GO; GO:0030155; P:regulation of cell adhesion; IEA:UniProt.
DR GO; GO:0051239; P:regulation of multicellular organismal process; IEA:UniProt.
DR GO; GO:0007165; P:signal transduction; ISS:UniProtKB.
DR CDD; cd13333; FERM_C_JAK2; 1.
DR CDD; cd05078; PTK_Jak2_rpt1; 1.
DR CDD; cd14205; PTKc_Jak2_rpt2; 1.
DR CDD; cd10379; SH2_Jak2; 1.
DR Gene3D; 2.30.29.30; -; 1.
DR Gene3D; 3.30.505.10; -; 1.
DR InterPro; IPR019749; Band_41_domain.
DR InterPro; IPR035963; FERM_2.
DR InterPro; IPR000299; FERM_domain.
DR InterPro; IPR041155; FERM_F1.
DR InterPro; IPR041046; FERM_F2.
DR InterPro; IPR041381; JAK1-3/TYK2_PHL_dom.
DR InterPro; IPR037838; JAK2_FERM_C-lobe.
DR InterPro; IPR035860; JAK2_SH2.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR011993; PH-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR035588; PTK_Jak2_rpt1.
DR InterPro; IPR035589; PTKc_Jak2_rpt2.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR000980; SH2.
DR InterPro; IPR036860; SH2_dom_sf.
DR InterPro; IPR008266; Tyr_kinase_AS.
DR InterPro; IPR020635; Tyr_kinase_cat_dom.
DR InterPro; IPR016251; Tyr_kinase_non-rcpt_Jak/Tyk2.
DR InterPro; IPR020693; Tyr_kinase_non-rcpt_Jak2.
DR Pfam; PF18379; FERM_F1; 1.
DR Pfam; PF18377; FERM_F2; 1.
DR Pfam; PF17887; Jak1_Phl; 1.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 2.
DR Pfam; PF00017; SH2; 1.
DR PIRSF; PIRSF000636; TyrPK_Jak; 1.
DR PRINTS; PR01823; JANUSKINASE.
DR PRINTS; PR01825; JANUSKINASE2.
DR PRINTS; PR00109; TYRKINASE.
DR SMART; SM00295; B41; 1.
DR SMART; SM00252; SH2; 1.
DR SMART; SM00219; TyrKc; 2.
DR SUPFAM; SSF47031; SSF47031; 1.
DR SUPFAM; SSF55550; SSF55550; 1.
DR SUPFAM; SSF56112; SSF56112; 2.
DR PROSITE; PS50057; FERM_3; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 2.
DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
DR PROSITE; PS50001; SH2; 1.
PE 2: Evidence at transcript level;
KW Adaptive immunity; ATP-binding; Chromatin regulator; Cytoplasm; Immunity;
KW Innate immunity; Kinase; Magnesium; Membrane; Metal-binding;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome; Repeat;
KW SH2 domain; Transferase; Tyrosine-protein kinase; Ubl conjugation.
FT CHAIN 1..1132
FT /note="Tyrosine-protein kinase JAK2"
FT /id="PRO_0000324094"
FT DOMAIN 37..380
FT /note="FERM"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00084"
FT DOMAIN 401..482
FT /note="SH2; atypical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00191"
FT DOMAIN 545..809
FT /note="Protein kinase 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 849..1126
FT /note="Protein kinase 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1..239
FT /note="Interaction with cytokine/interferon/growth hormone
FT receptors"
FT /evidence="ECO:0000250"
FT ACT_SITE 976
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10028"
FT BINDING 855..863
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 882
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 119
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q62120"
FT MOD_RES 372
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q62120"
FT MOD_RES 373
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q62120"
FT MOD_RES 523
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q62120"
FT MOD_RES 570
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:O60674"
FT MOD_RES 813
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q62120"
FT MOD_RES 868
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q62120"
FT MOD_RES 966
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q62120"
FT MOD_RES 972
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q62120"
FT MOD_RES 1007
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:O60674"
FT MOD_RES 1008
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:O60674"
SQ SEQUENCE 1132 AA; 130704 MW; 25EA1ADCB4B2B918 CRC64;
MGMACLTMTE MEGTSTSSIY QNGDISGNAN SMKQIDPVLL VYLYHSLGKS EADYLTFPSG
EYVAEEICIA ASKACGITPV YHNMFALMSE TERIWYPPNH VFHIDESTRH NVLYRIRFYF
PRWYCSGSNR AYRHGISRGA EAPLLDDFVM SYLFAQWRHD FVHGWIKVPV THETQEECLG
MAVLDMMRIA KENDQTPLAI YNSISYKTFL PKCIRAKIQD YHILTRKRIR YRFRRFIQQF
SQCKATARNL KLKYLINLET LQSAFYTEKF EVKEPGSGPS GEEIFATIII TGNGGIQWSR
GKHKESETLT EQDLQLYCDF PNIIDVSIKQ ANQEGSNESR VVTIHKQDGK NLEIELSSLR
EALSFVSLID GYYRLTADAH HYLCKEVAPP TVLENIQSNC HGPISMDFAI SKLKKAGNQT
GLYVLRCSPK DFNKYFLTFA VERENVIEYK HCLITKNENE EYNLSGTKKN FSSLKDLLNC
YQMETVRSDN IIFQFTKCCP PKPKDKSNLL VFRTNGVSDV PTSPTLQRPT HMNQMVFHKI
RNEDLIFNES LGQGTFTKIF KGVRREVGDY GQLHETEVLL KVLDKAHRNY SESFFEAASM
MSKLSHKHLV LNYGVCVCGD ENILVQEFVK FGSLDTYLKK NKNCINILWK LEVAKQLAWA
MHFLEENTLI HGNVCAKNIL LIREEDRKTG NPPFIKLSDP GISITVLPKD ILQERIPWVP
PECIENPKNL NLATDKWSFG TTLWEICSGG DKPLSALDSQ RKLQFYEDRH QLPAPKWAEL
ANLINNCMDY EPDFRPSFRA IIRDLNSLFT PDYELLTEND MLPNMRIGAL GFSGAFEDRD
PTQFEERHLK FLQQLGKGNF GSVEMCRYDP LQDNTGEVVA VKKLQHSTEE HLRDFEREIE
ILKSLQHDNI VKYKGVCYSA GRRNLKLIME YLPYGSLRDY LQKHKERIDH KKLLQYTSQI
CKGMEYLGTK RYIHRDLATR NILVENENRV KIGDFGLTKV LPQDKEYYKV KEPGESPIFW
YAPESLTESK FSVASDVWSF GVVLYELFTY IEKSKSPPAE FMRMIGNDKQ GQMIVFHLIE
LLKNNGRLPR PDGCPDEIYM IMTECWNNNV NQRPSFRDLA LRVDQIRDNM AG
