locus: 9p24

血液疾患

真性多血症(PV)、原発性骨髄線維症(MF)、本態性血小板血症(ET)の半数以上でJAK2遺伝子の点変異が認められている。

参考

1. JANUS KINASE 2; JAK2 - OMIM

http://omim.org/entry/147796

2. wiki en

http://en.wikipedia.org/wiki/Janus_kinase_2

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2019/06/07 04:27:19」(JST)

wiki en

[Wiki en表示]

Janus kinase 2 (commonly called JAK2) is a non-receptor tyrosine kinase. It is a member of the Janus kinase family and has been implicated in signaling by members of the type II cytokine receptor family (e.g. interferon receptors), the GM-CSF receptor family (IL-3R, IL-5R and GM-CSF-R), the gp130 receptor family (e.g., IL-6R), and the single chain receptors (e.g. Epo-R, Tpo-R, GH-R, PRL-R).^[5]^[6]

The distinguishing feature between janus kinase 2 and other JAK kinases is the lack of Src homology binding domains (SH2/SH3) and the presence of up to seven JAK homology domains (JH1-JH7). Nonetheless the terminal JH domains retain a high level of homology to tyrosine kinase domains. An interesting note is that only one of these carboxy-terminal JH domains retains full kinase function (JH1) while the other (JH2), previously thought to have no kinase functionality and accordingly termed a pseudokinase domain, has since been found to be catalytically active, albeit at only 10% that of the JH1 domain.^[7]^[8]

Loss of Jak2 is lethal by embryonic day 12 in mice.^[9]

JAK2 orthologs ^[10] have been identified in all mammals for which complete genome data are available.

Clinical significance

JAK2 gene fusions with the TEL(ETV6) (TEL-JAK2) and PCM1 genes have been found in patients suffering leukemia, particularly clonal eosinophilia forms of the disease.^[11]^[12]^[13]

Mutations in JAK2 have been implicated in polycythemia vera, essential thrombocythemia, and myelofibrosis as well as other myeloproliferative disorders.^[14] This mutation (V617F), a change of valine to phenylalanine at the 617 position, appears to render hematopoietic cells more sensitive to growth factors such as erythropoietin and thrombopoietin, because the receptors for these growth factors require JAK2 for signal transduction. An inhibitor of JAK2-STAT5, AZD1480, was pointed as having activity in primary and CRPC.^[15]

Jak2 mutation, when demonstrable, is one of the methods of diagnosing polycythemia vera.^[16]

Interactions

Janus kinase 2 has been shown to interact with:

DNAJA3,^[17]
EGFR,^[18]
EPOR,^[19]^[20]
FYN,^[21]
Grb2,^[22]^[23]
GHR,^[24]^[25]^[26]
IRS1,^[27]^[28]
IL12RB2,^[29]
IL5RA,^[30]
PIK3R1,^[31]
PPP2R4,^[31]
PTK2,^[32]^[33]
PTPN11,^[34]^[35]^[36]
PTPN6,^[37]^[38]
PRMT5,^[39]
SH2B1,^[40]^[41]
SHC1,^[42]^[43]
SOCS3,^[44]^[45]^[46]
STAT5A,^[47]^[48]
STAT5B,^[47]^[48]
STAM,^[49]
SOCS1,^[46]^[50]^[51]^[52]^[53]^[54]
TEC,^[55]^[56]
TNFRSF1A,^[57]
VAV1,^[58]^[59] and
YES1.^[31]

Prolactin signals through JAK2 are dependent on STAT5, and on the RUSH transcription factors.^[60]

References

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^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000024789 - Ensembl, May 2017
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External links

Janus+Kinase+2 at the US National Library of Medicine Medical Subject Headings (MeSH)

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1. 骨髄増殖性腫瘍の概要overview of the myeloproliferative neoplasms [show details]
…mutated genes in PV, ET, and PMF are JAK2, CALR, and MPL; estimates of their frequency follow : PV – 100 percent JAK2 mutations (exon 14 or 12) ET – 60 to 65 percent JAK2 mutation, 20 to 25 percent CALR mutation …
2. 赤血球増加症患者に対する診断的アプローチdiagnostic approach to the patient with polycythemia [show details]
…renal abnormalities. We suggest not testing for JAK2 mutation and/or bone marrow examination in all patients with polycythemia. We selectively perform JAK2 mutation testing in the following settings: Patients …
3. 先天性赤血球増多症および真性多血症の分子学的病因molecular pathogenesis of congenital polycythemic disorders and polycythemia vera [show details]
…with constitutive activation of the JAK2 tyrosine kinase (TK) domain. These findings documented that JAK2 has an oncogenic potential. Abnormal signaling in PV through JAK2 was first proposed in 2004 , followed …
4. 好酸球の生物学および好酸球増多症の原因eosinophil biology and causes of eosinophilia [show details]
…(FGFR1). Other recurrent abnormalities include fusion genes and point mutations involving JAK2, which encodes the JAK2 protein kinase . Depending on the stage of their disease and the organ(s) involved, patients…
5. 真性多血症の臨床症状および診断clinical manifestations and diagnosis of polycythemia vera [show details]
…houses the JAK2 gene, which carries a somatic point mutation in virtually all patients with PV . When sensitive quantitative assays are employed, 95 to 100 percent of patients with PV have a JAK2 (Janus …

English Journal

A triplex probe-based TaqMan qPCR assay for Calreticulin type I and II mutation detection.

Tang Y, Shi C, Wu Z, Fan N, Xu X, Kang Z, Zhang X, Ma W, Guan M.
Hematology (Amsterdam, Netherlands). 2019 Dec;24(1)26-31.
Calreticulin (CALR) exon 9 frameshift mutations have recently been identified in 30-40% of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF) without JAK2 or MPL mutations. We aimed to develop a qPCR assay to screen type I and II mutations of CALR. Three different fluoresce
PMID 30080988

Inhibition of protein nitration prevents cisplatin-induced inactivation of STAT3 and promotes anti-apoptotic signaling in organ of Corti cells.

Rosati R, Shahab M, Neumann WL, Jamesdaniel S.
Experimental cell research. 2019 Aug;381(1)105-111.
JAK/STAT pathway is one among the several oxidative stress-responsive signaling pathways that play a critical role in facilitating cisplatin-induced ototoxicity. Cisplatin treatment decreases the levels of cochlear LMO4, which acts as a scaffold for IL6-GP130 protein complex. Cisplatin-induced nitra
PMID 31078568

Increased autocrine interleukin-6 production is significantly associated with worse clinical outcome in patients with chronic lymphocytic leukemia.

Wang HQ, Jia L, Li YT, Farren T, Agrawal SG, Liu FT.
Journal of cellular physiology. 2019 Aug;234(8)13994-14006.
Chronic lymphocytic leukemia (CLL) remains incurable with current standard therapy. We have previously reported that an increased expression of interleukin-6 (IL-6) receptor CD126 leads to resistance of CLL cells to chemotherapy and worse prognosis for patients with CLL. In this study, we determine
PMID 30623437

Japanese Journal

招請講演骨髄増殖性腫瘍の病態と治療戦略 (第116回日本内科学会講演会(2019年) 新時代の内科学の創造 : 分化と統合,そして融合へ)

小松則夫
日本内科学会雑誌 108(臨増), 88-95,156, 2019-02-28
NAID 40021832441

Quercetin and its metabolite isorhamnetin promote glucose uptake through different signalling pathways in myotubes

Jiang Hao,Yamashita Yoko,Nakamura Asuka,Croft Kevin,Ashida Hitoshi
Scientific Reports (9), 2690, 2019-02-25
… However, treatment with siJAK3 did not affect isorhamnetin-induced GLUT4 translocation, indicating that isorhamnetin induced GLUT4 translocation mainly through JAK2, but not JAK3, signalling. … Thus, quercetin preferably activated the AMPK pathway and, accordingly, stimulated IRS1/PI3K/Akt signalling, while isorhamnetin activated the JAK2/STAT pathway. …
NAID 120006599101

骨髄増殖性腫瘍のマネジメント : ELN2018に基づく治療指針

竹中克斗
血液内科 = Hematology 78(1), 110-116, 2019-01
NAID 40021792483

Related Pictures

Jak and Daxter FIGURE 2 | Mechanism of activation of JAK2 JAK2 V617F activating mutation diagram Janus Kinase 2 (JAK2) Structure Jak2 Stat3 SCREENS ADDED: 26 May-2003 Jak and Daxter HD Collection - Release Jak2 V617f http://www.nature.com/nrd

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JAK2
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	5AEP, 2B7A, 2W1I, 2XA4, 3E62, 3E63, 3E64, 3FUP, 3IO7, 3IOK, 3JY9, 3KCK, 3KRR, 3LPB, 3Q32, 3RVG, 3TJC, 3TJD, 3UGC, 3ZMM, 4AQC, 4BBE, 4BBF, 4C61, 4C62, 4D0W, 4D0X, 4D1S, 4E4M, 4E6D, 4E6Q, 4F08, 4F09, 4FVP, 4FVQ, 4FVR, 4GFM, 4GMY, 4HGE, 4IVA, 4JI9, 4JIA, 4P7E, 4ZIM, 4YTC, 4YTF, 4YTH, 4YTI, 5CF4, 5CF5, 5CF6, 5CF8, 5I4N, 4Z32, 5L3A
Identifiers
Aliases	JAK2, JTK10, THCYT3, Janus kinase 2, MAX2
External IDs	OMIM: 147796 MGI: 96629 HomoloGene: 21033 GeneCards: JAK2
Gene location (Human)
Chr.	Chromosome 9 (human)
End	5,128,183 bp
Gene location (Mouse)
Chr.	Chromosome 19 (mouse)
End	29,313,080 bp
Gene ontology
Molecular function	• SH2 domain binding; • kinase activity; • receptor binding; • ATP binding; • growth hormone receptor binding; • interleukin-12 receptor binding; • metal ion binding; • heme binding; • histone kinase activity (H3-Y41 specific); • transferase activity; • histone binding; • protein binding; • protein tyrosine kinase activity; • protein kinase binding; • nucleotide binding; • Ras guanyl-nucleotide exchange factor activity; • non-membrane spanning protein tyrosine kinase activity; • identical protein binding; • protein kinase activity; • protein C-terminus binding; • type 1 angiotensin receptor binding; • acetylcholine receptor binding; • phosphatidylinositol 3-kinase binding; • insulin receptor substrate binding; • peptide hormone receptor binding;
Cellular component	• cytoplasm; • cytosol; • membrane; • extrinsic component of cytoplasmic side of plasma membrane; • caveola; • cytoskeleton; • cell nucleus; • nuclear matrix; • endosome lumen; • membrane raft; • endomembrane system; • nucleoplasm; • plasma membrane; • focal adhesion; • postsynapse; • glutamatergic synapse;
Biological process	• negative regulation of neuron apoptotic process; • intrinsic apoptotic signaling pathway in response to oxidative stress; • adaptive immune response; • interferon-gamma-mediated signaling pathway; • negative regulation of DNA binding; • tumor necrosis factor-mediated signaling pathway; • protein phosphorylation; • positive regulation of phosphoprotein phosphatase activity; • growth hormone receptor signaling pathway; • positive regulation of interleukin-1 beta production; • positive regulation of DNA binding; • mesoderm development; • activation of cysteine-type endopeptidase activity involved in apoptotic process; • negative regulation of cell proliferation; • apoptotic process; • regulation of apoptotic process; • positive regulation of cell activation; • positive regulation of protein import into nucleus, translocation; • mammary gland epithelium development; • extrinsic apoptotic signaling pathway; • axon regeneration; • activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway; • response to antibiotic; • positive regulation of nitric-oxide synthase biosynthetic process; • histone H3-Y41 phosphorylation; • response to oxidative stress; • response to tumor necrosis factor; • response to interleukin-12; • positive regulation of cell differentiation; • positive regulation of tumor necrosis factor production; • positive regulation of peptidyl-tyrosine phosphorylation; • erythrocyte differentiation; • autophosphorylation; • platelet-derived growth factor receptor signaling pathway; • positive regulation of cell-substrate adhesion; • positive regulation of growth hormone receptor signaling pathway; • G-protein coupled receptor signaling pathway; • cell differentiation; • JAK-STAT cascade involved in growth hormone signaling pathway; • positive regulation of inflammatory response; • phosphorylation; • immune system process; • positive regulation of sequence-specific DNA binding transcription factor activity; • negative regulation of cardiac muscle cell apoptotic process; • actin filament polymerization; • response to lipopolysaccharide; • regulation of inflammatory response; • peptidyl-tyrosine autophosphorylation; • enzyme linked receptor protein signaling pathway; • positive regulation of insulin secretion; • JAK-STAT cascade; • intracellular signal transduction; • negative regulation of cell-cell adhesion; • mineralocorticoid receptor signaling pathway; • negative regulation of heart contraction; • positive regulation of cell migration; • positive regulation of cytosolic calcium ion concentration; • positive regulation of nitric oxide biosynthetic process; • blood coagulation; • response to hydroperoxide; • MAPK cascade; • regulation of interferon-gamma-mediated signaling pathway; • regulation of cell proliferation; • positive regulation of cell proliferation; • hormone-mediated signaling pathway; • positive regulation of apoptotic process; • positive regulation of phosphatidylinositol 3-kinase signaling; • peptidyl-tyrosine phosphorylation; • cell migration; • signal transduction; • positive regulation of epithelial cell apoptotic process; • positive regulation of growth factor dependent skeletal muscle satellite cell proliferation; • innate immune response; • activation of MAPKK activity; • negative regulation of cell death; • positive regulation of vascular smooth muscle cell proliferation; • positive regulation of tyrosine phosphorylation of STAT protein; • activation of Janus kinase activity; • tyrosine phosphorylation of STAT protein; • interleukin-12-mediated signaling pathway; • cytokine-mediated signaling pathway; • interleukin-23-mediated signaling pathway; • interleukin-6-mediated signaling pathway; • interleukin-27-mediated signaling pathway; • interleukin-35-mediated signaling pathway; • chromatin organization; • regulation of JAK-STAT cascade; • regulation of nitric oxide biosynthetic process; • positive regulation of Ras protein signal transduction; • modulation of chemical synaptic transmission; • postsynapse to nucleus signaling pathway; • positive regulation of cold-induced thermogenesis; • microglial cell activation; • positive regulation of receptor biosynthetic process; • positive regulation of tumor necrosis factor biosynthetic process; • positive regulation of MHC class II biosynthetic process; • positive regulation of interleukin-1 beta biosynthetic process;
	Sources:Amigo / QuickGO
Orthologs
	3717
	16452
	ENSG00000096968
	ENSMUSG00000024789
	O60674
	Q62120
NM_004972; NM_001322194; NM_001322195; NM_001322196; NM_001322198;
	NM_001322199; NM_001322204
	NM_001048177; NM_008413
NP_001309123; NP_001309124; NP_001309125; NP_001309127; NP_001309128;
	NP_001309133; NP_004963
	NP_001041642; NP_032439
	Wikidata
View/Edit Human	View/Edit Mouse

　　[★]

英: prolactin (Z), PRL, lactotrophic hormone (Z)
関: ホルモン、下垂体前葉ホルモン

分類

下垂体ホルモン

性状

ペプチド
199 aa., 198aa 21.5kDa(HIM.2204)
成長ホルモン、hPL(human placental lactogen)に構造が似る　→　common GH-PRL-hPL precursor gene on chromosome 6

産生組織

下垂体前葉：lactrope(20%を占める)で産生される。lactropeはsomatotropeと同じ前駆細胞に由来するので、GHとPRLを産生する線種もある。lactropeのpopulationはエストロゲンの影響下にあって、また妊娠のlast two trimestersおよび授乳期の最初の2,3ヶ月に過形成が起こる。(HIM.2204)
わずかに下記組織で産生される (SP.888)

胎盤脱落膜細胞、リンパ球、視床下部神経細胞

標的組織

乳腺

生理作用

プロラクチンの生理作用はエストロゲンにより阻害される(SP.888)　←　分娩後に初めて乳汁産生が起こる

乳汁産生促進

乳腺上皮細胞の増殖↑
乳汁産生↑(カゼイン・ラクトアルブミン・ラクトグロブリン・乳糖・脂肪酸の産生↑)

HIM.2204

プロラクチンは乳汁分泌を維持し、生殖機能を低下させ、性的衝動を減退させる。
これらの機能は、母体の乳汁分泌を持続し妊娠によって中断しないことを確実にすることにかなう。
プロラクチンは視床下部のGnRHや下垂体でのGnHの分泌を抑制し、男女ともに視床下部のステロイド合成を減少させる。
卵巣では、卵胞形成を阻止し、顆粒層細胞のアロマターゼ活性を抑制し、低エストロゲン症と無排卵をきたす。
プロラクチンは黄体退縮作用を持ち、月経周期の黄体周を短縮させ、あるいは不十分にする。
これらのホルモンの変化により性欲が減退し、生殖力が低下する。

作用機序

プロラクチン受容体→JAK2-STAT5→遺伝子発現

分泌調節

プロラクチンの分泌制御はユニークであり、ドパミンによるD2受容体を介した抑制を受ける。
プロラクチンは視床下部に対して抑制的に作用し、間接的に下垂体前葉からのプロラクチン放出が抑制される　(短環フィードバック)
視床下部からドーパミンが放出され、下垂体前葉に対し抑制的に作用する。

SP.889改変

分泌促進	分泌抑制
吸乳エストロゲン妊娠睡眠ストレスプロラクチン放出因子セロトニン作動薬ドーパミン受容体遮断薬 TRH	ドーパミン受容体作動薬プロラクチン

HIM.2204

パルス状に分泌
REM睡眠時に分泌↑　　←　成長ホルモンと似ている？
血中濃度のピークは朝方(4-6時)で、30ng/ml
半減期は50分

妊娠・出産との関連

授乳する場合、出産後3-4ヶ月かかって緩やかに下降。　→　同時期の月経再開と関連

基準値

検査の本？

小児(10歳まで)　1.2-12ng/ml
成人女性　1.5-15ng/ml
成人男性　1.5-10ng/ml
高齢者(70歳以上)　1.2-15ng/ml
以上、WHO　1st IRP-PRL(75/504)を標準品とした値。なお、妊婦、産褥期には高値となりこの基準値はあてはまらない

HIM.2204

10-25 ng/ml (女性)
10-20 ng/ml (男性)

検査

プロラクチン分泌促進テスト：TRHテスト
プロラクチン分泌抑制テスト：ブロモクリプチン負荷テスト

臨床関連

高プロラクチン血症

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000096968 - Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000024789 - Ensembl, May 2017

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[4] "Mouse PubMed Reference:".

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[OrthoMaM-10] "OrthoMaM phylogenetic marker: JAK2 coding sequence".

[pmid9360930-11] Lacronique V, Boureux A, Valle VD, Poirel H, Quang CT, Mauchauffé M, Berthou C, Lessard M, Berger R, Ghysdael J, Bernard OA (November 1997). "A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia". Science. 278 (5341): 1309–12. doi:10.1126/science.278.5341.1309. PMID 9360930.

[pmid15805263-12] Reiter A, Walz C, Watmore A, Schoch C, Blau I, Schlegelberger B, Berger U, Telford N, Aruliah S, Yin JA, Vanstraelen D, Barker HF, Taylor PC, O'Driscoll A, Benedetti F, Rudolph C, Kolb HJ, Hochhaus A, Hehlmann R, Chase A, Cross NC (April 2005). "The t(8;9)(p22;p24) is a recurrent abnormality in chronic and acute leukemia that fuses PCM1 to JAK2". Cancer Research. 65 (7): 2662–7. doi:10.1158/0008-5472.CAN-04-4263. PMID 15805263.

[pmid28028030-13] Reiter A, Gotlib J (2017). "Myeloid neoplasms with eosinophilia". Blood. 129 (6): 704–714. doi:10.1182/blood-2016-10-695973. PMID 28028030.

[pmid15858187-14] Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A, Cazzola M, Skoda RC (April 2005). "A gain-of-function mutation of JAK2 in myeloproliferative disorders". The New England Journal of Medicine. 352 (17): 1779–90. doi:10.1056/NEJMoa051113. PMID 15858187.

[pmid23942095-15] Gu L, Liao Z, Hoang DT, Dagvadorj A, Gupta S, Blackmon S, Ellsworth E, Talati P, Leiby B, Zinda M, Lallas CD, Trabulsi EJ, McCue P, Gomella L, Huszar D, Nevalainen MT (October 2013). "Pharmacologic inhibition of Jak2-Stat5 signaling By Jak2 inhibitor AZD1480 potently suppresses growth of both primary and castrate-resistant prostate cancer". Clinical Cancer Research. 19 (20): 5658–74. doi:10.1158/1078-0432.CCR-13-0422. PMC 6021137. PMID 23942095.

[pmid21674578-16] Scott LM (August 2011). "The JAK2 exon 12 mutations: a comprehensive review". American Journal of Hematology. 86 (8): 668–76. doi:10.1002/ajh.22063. PMID 21674578.

[pmid11679576-17] Sarkar S, Pollack BP, Lin KT, Kotenko SV, Cook JR, Lewis A, Pestka S (December 2001). "hTid-1, a human DnaJ protein, modulates the interferon signaling pathway". The Journal of Biological Chemistry. 276 (52): 49034–42. doi:10.1074/jbc.M103683200. PMID 11679576.

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[pmid11779507-19] Huang LJ, Constantinescu SN, Lodish HF (December 2001). "The N-terminal domain of Janus kinase 2 is required for Golgi processing and cell surface expression of erythropoietin receptor". Molecular Cell. 8 (6): 1327–38. doi:10.1016/S1097-2765(01)00401-4. PMID 11779507.

[pmid8343951-20] Witthuhn BA, Quelle FW, Silvennoinen O, Yi T, Tang B, Miura O, Ihle JN (July 1993). "JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin". Cell. 74 (2): 227–36. doi:10.1016/0092-8674(93)90414-L. PMID 8343951.

[pmid10551884-21] Sayeski PP, Ali MS, Safavi A, Lyles M, Kim SO, Frank SJ, Bernstein KE (November 1999). "A catalytically active Jak2 is required for the angiotensin II-dependent activation of Fyn". The Journal of Biological Chemistry. 274 (46): 33131–42. doi:10.1074/jbc.274.46.33131. PMID 10551884.

[pmid7500025-22] Chauhan D, Kharbanda SM, Ogata A, Urashima M, Frank D, Malik N, Kufe DW, Anderson KC (December 1995). "Oncostatin M induces association of Grb2 with Janus kinase JAK2 in multiple myeloma cells". The Journal of Experimental Medicine. 182 (6): 1801–6. doi:10.1084/jem.182.6.1801. PMC 2192257. PMID 7500025.

[pmid8536716-23] Giorgetti-Peraldi S, Peyrade F, Baron V, Van Obberghen E (December 1995). "Involvement of Janus kinases in the insulin signaling pathway". European Journal of Biochemistry / FEBS. 234 (2): 656–60. doi:10.1111/j.1432-1033.1995.656_b.x. PMID 8536716.

[pmid7540178-24] Frank SJ, Yi W, Zhao Y, Goldsmith JF, Gilliland G, Jiang J, Sakai I, Kraft AS (June 1995). "Regions of the JAK2 tyrosine kinase required for coupling to the growth hormone receptor". The Journal of Biological Chemistry. 270 (24): 14776–85. doi:10.1074/jbc.270.24.14776. PMID 7540178.

[pmid8063815-25] VanderKuur JA, Wang X, Zhang L, Campbell GS, Allevato G, Billestrup N, Norstedt G, Carter-Su C (August 1994). "Domains of the growth hormone receptor required for association and activation of JAK2 tyrosine kinase". The Journal of Biological Chemistry. 269 (34): 21709–17. PMID 8063815.

[pmid10502458-26] Hellgren G, Jansson JO, Carlsson LM, Carlsson B (June 1999). "The growth hormone receptor associates with Jak1, Jak2 and Tyk2 in human liver". Growth Hormone & IGF Research. 9 (3): 212–8. doi:10.1054/ghir.1999.0111. PMID 10502458.

[pmid9492017-27] Gual P, Baron V, Lequoy V, Van Obberghen E (March 1998). "Interaction of Janus kinases JAK-1 and JAK-2 with the insulin receptor and the insulin-like growth factor-1 receptor". Endocrinology. 139 (3): 884–93. doi:10.1210/endo.139.3.5829. PMID 9492017.

[pmid11208867-28] Kawazoe Y, Naka T, Fujimoto M, Kohzaki H, Morita Y, Narazaki M, Okumura K, Saitoh H, Nakagawa R, Uchiyama Y, Akira S, Kishimoto T (January 2001). "Signal transducer and activator of transcription (STAT)-induced STAT inhibitor 1 (SSI-1)/suppressor of cytokine signaling 1 (SOCS1) inhibits insulin signal transduction pathway through modulating insulin receptor substrate 1 (IRS-1) phosphorylation". The Journal of Experimental Medicine. 193 (2): 263–9. doi:10.1084/jem.193.2.263. PMC 2193341. PMID 11208867.

[pmid10198225-29] Yamamoto K, Shibata F, Miura O, Kamiyama R, Hirosawa S, Miyasaka N (April 1999). "Physical interaction between interleukin-12 receptor beta 2 subunit and Jak2 tyrosine kinase: Jak2 associates with cytoplasmic membrane-proximal region of interleukin-12 receptor beta 2 via amino-terminus". Biochemical and Biophysical Research Communications. 257 (2): 400–4. doi:10.1006/bbrc.1999.0479. PMID 10198225.

[pmid9516124-30] Ogata N, Kouro T, Yamada A, Koike M, Hanai N, Ishikawa T, Takatsu K (April 1998). "JAK2 and JAK1 constitutively associate with an interleukin-5 (IL-5) receptor alpha and betac subunit, respectively, and are activated upon IL-5 stimulation". Blood. 91 (7): 2264–71. PMID 9516124.

[pmid8702385-31] Fuhrer DK, Yang YC (July 1996). "Complex formation of JAK2 with PP2A, P13K, and Yes in response to the hematopoietic cytokine interleukin-11". Biochemical and Biophysical Research Communications. 224 (2): 289–96. doi:10.1006/bbrc.1996.1023. PMID 8702385.

[pmid9553131-32] Zhu T, Goh EL, Lobie PE (April 1998). "Growth hormone stimulates the tyrosine phosphorylation and association of p125 focal adhesion kinase (FAK) with JAK2. Fak is not required for stat-mediated transcription". The Journal of Biological Chemistry. 273 (17): 10682–9. doi:10.1074/jbc.273.17.10682. PMID 9553131.

[pmid10925297-33] Ryu H, Lee JH, Kim KS, Jeong SM, Kim PH, Chung HT (August 2000). "Regulation of neutrophil adhesion by pituitary growth hormone accompanies tyrosine phosphorylation of Jak2, p125FAK, and paxillin". Journal of Immunology. 165 (4): 2116–23. doi:10.4049/jimmunol.165.4.2116. PMID 10925297.

[pmid8995399-34] Yin T, Shen R, Feng GS, Yang YC (January 1997). "Molecular characterization of specific interactions between SHP-2 phosphatase and JAK tyrosine kinases". The Journal of Biological Chemistry. 272 (2): 1032–7. doi:10.1074/jbc.272.2.1032. PMID 8995399.

[pmid8639815-35] Tauchi T, Damen JE, Toyama K, Feng GS, Broxmeyer HE, Krystal G (June 1996). "Tyrosine 425 within the activated erythropoietin receptor binds Syp, reduces the erythropoietin required for Syp tyrosine phosphorylation, and promotes mitogenesis". Blood. 87 (11): 4495–501. PMID 8639815.

[pmid8912646-36] Maegawa H, Kashiwagi A, Fujita T, Ugi S, Hasegawa M, Obata T, Nishio Y, Kojima H, Hidaka H, Kikkawa R (November 1996). "SHPTP2 serves adapter protein linking between Janus kinase 2 and insulin receptor substrates". Biochemical and Biophysical Research Communications. 228 (1): 122–7. doi:10.1006/bbrc.1996.1626. PMID 8912646.

[pmid8943354-37] Jiao H, Berrada K, Yang W, Tabrizi M, Platanias LC, Yi T (December 1996). "Direct association with and dephosphorylation of Jak2 kinase by the SH2-domain-containing protein tyrosine phosphatase SHP-1". Molecular and Cellular Biology. 16 (12): 6985–92. doi:10.1128/mcb.16.12.6985. PMC 231702. PMID 8943354.

[pmid10772872-38] Wu DW, Stark KC, Dunnington D, Dillon SB, Yi T, Jones C, Pelus LM (February 2000). "SH2-Containing protein tyrosine phosphatase-1 (SHP-1) association with Jak2 in UT-7/Epo cells". Blood Cells, Molecules & Diseases. 26 (1): 15–24. doi:10.1006/bcmd.2000.0273. PMID 10772872.

[pmid10531356-39] Pollack BP, Kotenko SV, He W, Izotova LS, Barnoski BL, Pestka S (October 1999). "The human homologue of the yeast proteins Skb1 and Hsl7p interacts with Jak kinases and contains protein methyltransferase activity". The Journal of Biological Chemistry. 274 (44): 31531–42. doi:10.1074/jbc.274.44.31531. PMID 10531356.

[pmid9343427-40] Rui L, Mathews LS, Hotta K, Gustafson TA, Carter-Su C (November 1997). "Identification of SH2-Bbeta as a substrate of the tyrosine kinase JAK2 involved in growth hormone signaling". Molecular and Cellular Biology. 17 (11): 6633–44. doi:10.1128/mcb.17.11.6633. PMC 232517. PMID 9343427.

[pmid12370803-41] Xie S, Lin H, Sun T, Arlinghaus RB (October 2002). "Jak2 is involved in c-Myc induction by Bcr-Abl". Oncogene. 21 (47): 7137–46. doi:10.1038/sj.onc.1205942. PMID 12370803.

[pmid7535773-42] VanderKuur J, Allevato G, Billestrup N, Norstedt G, Carter-Su C (March 1995). "Growth hormone-promoted tyrosyl phosphorylation of SHC proteins and SHC association with Grb2". The Journal of Biological Chemistry. 270 (13): 7587–93. doi:10.1074/jbc.270.13.7587. PMID 7535773.

[pmid9126968-43] Giordano V, De Falco G, Chiari R, Quinto I, Pelicci PG, Bartholomew L, Delmastro P, Gadina M, Scala G (May 1997). "Shc mediates IL-6 signaling by interacting with gp130 and Jak2 kinase". Journal of Immunology. 158 (9): 4097–103. PMID 9126968.

[pmid10882725-44] Sasaki A, Yasukawa H, Shouda T, Kitamura T, Dikic I, Yoshimura A (September 2000). "CIS3/SOCS-3 suppresses erythropoietin (EPO) signaling by binding the EPO receptor and JAK2". The Journal of Biological Chemistry. 275 (38): 29338–47. doi:10.1074/jbc.M003456200. PMID 10882725.

[pmid10421843-45] Sasaki A, Yasukawa H, Suzuki A, Kamizono S, Syoda T, Kinjyo I, Sasaki M, Johnston JA, Yoshimura A (June 1999). "Cytokine-inducible SH2 protein-3 (CIS3/SOCS3) inhibits Janus tyrosine kinase by binding through the N-terminal kinase inhibitory region as well as SH2 domain". Genes to Cells. 4 (6): 339–51. doi:10.1046/j.1365-2443.1999.00263.x. PMID 10421843.

[pmid9344848-46] Masuhara M, Sakamoto H, Matsumoto A, Suzuki R, Yasukawa H, Mitsui K, Wakioka T, Tanimura S, Sasaki A, Misawa H, Yokouchi M, Ohtsubo M, Yoshimura A (October 1997). "Cloning and characterization of novel CIS family genes". Biochemical and Biophysical Research Communications. 239 (2): 439–46. doi:10.1006/bbrc.1997.7484. PMID 9344848.

[pmid9575217-47] Barahmand-Pour F, Meinke A, Groner B, Decker T (May 1998). "Jak2-Stat5 interactions analyzed in yeast". The Journal of Biological Chemistry. 273 (20): 12567–75. doi:10.1074/jbc.273.20.12567. PMID 9575217.

[pmid9047382-48] Fujitani Y, Hibi M, Fukada T, Takahashi-Tezuka M, Yoshida H, Yamaguchi T, Sugiyama K, Yamanaka Y, Nakajima K, Hirano T (February 1997). "An alternative pathway for STAT activation that is mediated by the direct interaction between JAK and STAT". Oncogene. 14 (7): 751–61. doi:10.1038/sj.onc.1200907. PMID 9047382.

[pmid9133424-49] Takeshita T, Arita T, Higuchi M, Asao H, Endo K, Kuroda H, Tanaka N, Murata K, Ishii N, Sugamura K (April 1997). "STAM, signal transducing adaptor molecule, is associated with Janus kinases and involved in signaling for cell growth and c-myc induction". Immunity. 6 (4): 449–57. doi:10.1016/S1074-7613(00)80288-5. PMID 9133424.

[pmid10064597-50] Yasukawa H, Misawa H, Sakamoto H, Masuhara M, Sasaki A, Wakioka T, Ohtsuka S, Imaizumi T, Matsuda T, Ihle JN, Yoshimura A (March 1999). "The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop". The EMBO Journal. 18 (5): 1309–20. doi:10.1093/emboj/18.5.1309. PMC 1171221. PMID 10064597.

[pmid11713228-51] Dif F, Saunier E, Demeneix B, Kelly PA, Edery M (December 2001). "Cytokine-inducible SH2-containing protein suppresses PRL signaling by binding the PRL receptor". Endocrinology. 142 (12): 5286–93. doi:10.1210/endo.142.12.8549. PMID 11713228.

[pmid9202126-52] Endo TA, Masuhara M, Yokouchi M, Suzuki R, Sakamoto H, Mitsui K, Matsumoto A, Tanimura S, Ohtsubo M, Misawa H, Miyazaki T, Leonor N, Taniguchi T, Fujita T, Kanakura Y, Komiya S, Yoshimura A (June 1997). "A new protein containing an SH2 domain that inhibits JAK kinases". Nature. 387 (6636): 921–4. doi:10.1038/43213. PMID 9202126.

[pmid10455112-53] Pezet A, Favre H, Kelly PA, Edery M (August 1999). "Inhibition and restoration of prolactin signal transduction by suppressors of cytokine signaling". The Journal of Biological Chemistry. 274 (35): 24497–502. doi:10.1074/jbc.274.35.24497. PMID 10455112.

[pmid11971965-54] Ungureanu D, Saharinen P, Junttila I, Hilton DJ, Silvennoinen O (May 2002). "Regulation of Jak2 through the ubiquitin-proteasome pathway involves phosphorylation of Jak2 on Y1007 and interaction with SOCS-1". Molecular and Cellular Biology. 22 (10): 3316–26. doi:10.1128/MCB.22.10.3316-3326.2002. PMC 133778. PMID 11971965.

[pmid9178903-55] Takahashi-Tezuka M, Hibi M, Fujitani Y, Fukada T, Yamaguchi T, Hirano T (May 1997). "Tec tyrosine kinase links the cytokine receptors to PI-3 kinase probably through JAK". Oncogene. 14 (19): 2273–82. doi:10.1038/sj.onc.1201071. PMID 9178903.

[pmid9473212-56] Yamashita Y, Watanabe S, Miyazato A, Ohya Ki, Ikeda U, Shimada K, Komatsu N, Hatake K, Miura Y, Ozawa K, Mano H (March 1998). "Tec and Jak2 kinases cooperate to mediate cytokine-driven activation of c-fos transcription". Blood. 91 (5): 1496–507. PMID 9473212.

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[pmid9162069-58] Shigematsu H, Iwasaki H, Otsuka T, Ohno Y, Arima F, Niho Y (May 1997). "Role of the vav proto-oncogene product (Vav) in erythropoietin-mediated cell proliferation and phosphatidylinositol 3-kinase activity". The Journal of Biological Chemistry. 272 (22): 14334–40. doi:10.1074/jbc.272.22.14334. PMID 9162069.

[pmid7530656-59] "Findings of scientific misconduct". NIH Guide for Grants and Contracts / U.S. Department of Health, Education, and Welfare. 24 (42): 1–2. December 1995. PMC 4259583. PMID 7495607.

[pmid20562009-60] Helmer RA, Panchoo M, Dertien JS, Bhakta SM, Hewetson A, Chilton BS (August 2010). "Prolactin-induced Jak2 phosphorylation of RUSH: a key element in Jak/RUSH signaling". Molecular and Cellular Endocrinology. 325 (1–2): 143–9. doi:10.1016/j.mce.2010.05.010. PMC 2902710. PMID 20562009.

v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)

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JAK2

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