酪氨酸激酶2

酪氨酸激酶2
已知的結構
PDB	直系同源搜索: PDBe RCSB
PDBID列表
	3LXN、3LXP、3NYX、3NZ0、3ZON、4GFO、4GIH、4GII、4GJ2、4GJ3、4GVJ、4OLI、4PO6、4PY1、4WOV、5C01、5C03、5F20、5F1Z
識別號
别名	TYK2；, IMD35, JTK1, tyrosine kinase 2, Non-receptor tyrosine-protein kinase
外部ID	OMIM：176941 MGI：1929470 HomoloGene：20712 GeneCards：TYK2
相關疾病
	類風濕性關節炎、1型糖尿病、銀屑病、susceptibility to infection due to TYK2 deficiency
為以下藥物的標靶
	鲁索利替尼
基因位置（人类）
染色体	19號染色體
终止	10,380,572 bp
基因位置（小鼠）
染色体	小鼠9号染色体
终止	21,042,539 bp
RNA表达模式
	查阅更多表达数据
基因本體
分子功能	• 轉移酶活性; • 核苷酸結合; • 蛋白激酶活性; • type 1 angiotensin receptor binding; • growth hormone receptor binding; • 激酶活性; • 血浆蛋白结合; • protein tyrosine kinase activity; • ATP結合; • non-membrane spanning protein tyrosine kinase activity;
細胞組分	• 細胞質; • 细胞质基质; • 膜; • extrinsic component of cytoplasmic side of plasma membrane; • 外排體; • 细胞骨架; • 细胞核;
生物學過程	• 细胞分化; • intracellular signal transduction; • 磷酸化; • transmembrane receptor protein tyrosine kinase signaling pathway; • protein phosphorylation; • regulation of type I interferon-mediated signaling pathway; • regulation of cell population proliferation; • type I interferon signaling pathway; • peptidyl-tyrosine autophosphorylation; • 先天免疫系統; • 细胞迁移; • interleukin-12-mediated signaling pathway; • peptidyl-tyrosine phosphorylation; • cytokine-mediated signaling pathway; • interleukin-23-mediated signaling pathway; • interleukin-27-mediated signaling pathway;
	Sources:Amigo / QuickGO
直系同源
	7297
	54721
	ENSG00000105397
	ENSMUSG00000032175
	P29597
	Q9R117
	NM_003331
	NM_001205312; NM_018793
	NP_003322
	NP_001192241; NP_061263
	維基數據
檢視/編輯人類	檢視/編輯小鼠

非受体酪氨酸激酶2（英語：Non-receptor tyrosine-protein kinase，TYK2）是人类基因组中TYK2基因所编码的酶^[7]^[8]。

TYK2是JAK家族中第一个被报导的（该家族的其它成员有JAK1、JAK2和JAK3）^[9]，与干扰素α、IL-6、IL-10和IL-12的信号相关。

功能

酪氨酸激酶2是TYK2基因编码的酪氨酸激酶中JAK激酶家族（JAKs）的一个成员蛋白。该蛋白与I型或II型细胞因子受体的胞质结构域结合，并通过磷酸化受体亚基来传递细胞因子的信号。该酶参与干扰素α和β产生的信号通路，因此也可能在抗病毒免疫中扮演一个角色^[8]。

细胞因子通过调节免疫细胞以及其它系统的细胞的存活、增殖、分化以及功能在免疫与炎症中起关键作用^[10]。因此，以细胞因子及其受体为靶标是治疗这类疾病的有效手段。白细胞介素、干扰素和促红细胞生成素等细胞因子正是通过I型和II型细胞因子受体与JAK家族的激酶结合来传递胞内信号。^[11]

哺乳动物的JAK激酶家族拥有四个成员：JAK1、JAK2、JAK3和酪氨酸激酶2（TYK2）^[9]。Jak激酶和细胞因子信号之间关系的第一次阐明是在筛选I型干扰素（英语：interferon type I）（IFN-1）信号相关基因时，鉴别出Tyk2是细胞因子受体进行一系列激活必要组件^[12]。而与早先在小鼠模型分析的基础上鉴定出的Tyk2对IL-12与I型干扰素信号的介导相比，Tyk2在人类基因组中的功能更为广泛和深刻。TYK2缺陷已在人类细胞中比在小鼠细胞的影响更大，在干扰素α和β以及IL-12之外，Tyk2还对IL-23、IL-10以及IL-6信号的转导起重要作用。因此，对于与gp-130受体链相结合的IL-6类细胞因子，包括IL-6、IL-11、IL-27、IL-31、制瘤素（英语：MOncostatin M）（OSM）、睫状神经营养因子（英语：ciliary neurotrophic factor）、心肌营养素1（英语：cardiotrophin 1）、心肌营养素样细胞因子因子（英语：CLCF1）以及LIF，Tyk2都具有信号传导作用。近来由发现了IL-12和IL-23在激活Tyk2的过程中使用了相同的配体与受体亚基。

IL-10是一个关键的抗炎性细胞因子，IL-10基因敲除的小鼠会遭受致命的全身性自體免疫性疾病。Tyk2由IL-10激活它的缺乏会影响细胞生成和响应IL-10的能力^[13]。在一般生理条件下，免疫细胞会受到许多种细胞因子的调节作用。现在已经清楚的是，这些不同的细胞因子信号在通过JAK–STAT信号通路时，会发生相互串扰^[14]。

炎症上的機制

目前普遍認為动脉粥样硬化肇因於發炎現象中的分子与细胞变化^[15]，而血管發炎可能是由血管收縮素II（Angiotensin II）的表現增加所致。發炎的血管會在局部分泌白細胞介素6（英语：Interleukin 6）（Interleukin 6，IL-6），IL-6是一種細胞激素，會促進血管收縮素II合成及分泌，和透過JAK-STAT信號通路促進肝臟的血管新生作用。

JAK/STAT3途徑會被目標細胞膜上的高親和性蛋白受體白細胞介素6受體（英语：Interleukin-6 receptor）（Interleukin-6 receptor，IL-6R）致活，參與這個連鎖反應的蛋白，包含了醣蛋白130（英语：glycoprotein 130）（glycoprotein 130，gp-130）和酪胺酸激酶（JAK1、JAK2和Tyk2）^[16]。

在慢性哮喘患者的肺中，細胞因子白細胞介素4（Interleukin 4，IL-4）和白細胞介素13（英语：Interleukin 13）（Interleukin 13，IL-13）的濃度會升高。經由IL-4/IL-13複合物的信息途徑被認為是由白細胞介素6受體（英语：interleukin-4 receptor）（Interleukin-6 receptor，IL-4Rα），其中受體包含了JAK-1和Tyk2等激酶。^[17]

從缺乏Tyk2的小鼠（Tyk2^-/-）身上，我們可以觀察到Tyk2對於類風溼性關節炎的發生所造成的影響^[18]。Tyk2^-/-的小鼠對於低劑量的干擾素-α （IFN-α）缺乏反應性，但在高劑量的 IFN-α和IFN-β作用下，反應仍然是正常的^[14]^[19]。另外，這些小鼠對於IL-6和IL-10的作用反應正常，可見Tyk2對於IL-6和IL-10的傳訊調節上市非必要的，且在IFN-α的傳訊上也並不是扮演非常主要的角色。

雖然Tyk2^-/-的小鼠表型正常，但他們在發炎反應中仍然有許多不正常的症狀^[20]。最明顯的是這些小鼠的巨噬細胞不會受到脂多糖（Lipopolysaccharide，LPS）的刺激而釋放出一氧化氮。對於這LPS信息傳送的分子機制，進一步的研究發現，Tyk2和IFN-β的缺失會阻抗脂多糖誘導內毒素性休克（endotoxin shock），而STAT1缺失的小鼠則比較容易受到感染^[21]。

Tyk2抑制劑的發展可能可以作為治療類風溼性關節炎的藥品^[22]。

臨床上的重要性

TYK2基因的突變與高免疫球蛋白E症候群（英语：Hyper-IgE syndrome）（Hyperimmunoglobulin E syndrome，HIES），一種造成血漿中免疫球蛋白IgE濃度不正常升高的疾病相关。^[23]^[24]^[25]

交互作用

酪氨酸激酶2已知能与FYN^[26]、PTPN6^[27]、IFNAR1^[28]^[29]、Ku80^[30]以及GNB2L1^[31]发生相互作用。

参考文献

^ 與酪氨酸激酶2相關的疾病；在維基數據上查看/編輯參考.
^ 對酪氨酸激酶2起作用的藥物；在維基數據上查看/編輯參考.
^ ^3.0 ^3.1 ^3.2 GRCh38: Ensembl release 89: ENSG00000105397 - Ensembl, May 2017
^ ^4.0 ^4.1 ^4.2 GRCm38: Ensembl release 89: ENSMUSG00000032175 - Ensembl, May 2017
^ Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Krolewski JJ, Lee R, Eddy R, Shows TB, Dalla-Favera R. Identification and chromosomal mapping of new human tyrosine kinase genes. Oncogene. March 1990, 5 (3): 277–82. PMID 2156206.
^ ^8.0 ^8.1 Entrez Gene: TYK2 tyrosine kinase 2. （原始内容存档于2019-06-14）.
^ ^9.0 ^9.1 Stark GR, Kerr IM, Williams BR, Silverman RH, Schreiber RD. How cells respond to interferons. Annu. Rev. Biochem. 1998, 67 (1): 227–64. PMID 9759489. doi:10.1146/annurev.biochem.67.1.227.
^ Nicola, Nicos. Guidebook to cytokines and their receptors. Oxford [Oxfordshire]: Oxford University Press. 1994. ISBN 0-19-859947-1.
^ Kubo M, Hanada T, Yoshimura A. Suppressors of cytokine signaling and immunity. Nat. Immunol. December 2003, 4 (12): 1169–76. PMID 14639467. doi:10.1038/ni1012.
^ Velazquez L, Fellous M, Stark GR, Pellegrini S. A protein tyrosine kinase in the interferon alpha/beta signaling pathway. Cell. July 1992, 70 (2): 313–22. PMID 1386289. doi:10.1016/0092-8674(92)90105-L.
^ Shaw MH, Freeman GJ, Scott MF; et al. Tyk2 negatively regulates adaptive Th1 immunity by mediating IL-10 signaling and promoting IFN-γ-dependent IL-10 reactivation. J. Immunol. June 2006, 176 (12): 7263–71 [2013-10-22]. PMID 16751369. （原始内容存档于2019-06-14）.
^ ^14.0 ^14.1 Shimoda K, Kato K, Aoki K; et al. Tyk2 plays a restricted role in IFN alpha signaling, although it is required for IL-12-mediated T cell function. Immunity. October 2000, 13 (4): 561–71 [2013-10-22]. PMID 11070174. doi:10.1016/S1074-7613(00)00055-8. （原始内容存档于2019-06-14）. 引证错误：带有name属性“pmid11070174”的<ref>标签用不同内容定义了多次
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^ Potla R, Koeck T, Wegrzyn J, Cherukuri S, Shimoda K, Baker DP, Wolfman J, Planchon SM, Esposito C, Hoit B, Dulak J, Wolfman A, Stuehr D, Larner AC. Tyk2 tyrosine kinase expression is required for the maintenance of mitochondrial respiration in primary pro-B lymphocytes. Mol. Cell. Biol. November 2006, 26 (22): 8562–71. PMC 1636766 . PMID 16982690. doi:10.1128/MCB.00497-06.
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^ Thompson JE. JAK protein kinase inhibitors. Drug News Perspect. June 2005, 18 (5): 305–10. PMID 16193102. doi:10.1358/dnp.2005.18.5.904198.
^ Minegishi Y, Saito M, Morio T, Watanabe K, Agematsu K, Tsuchiya S, Takada H, Hara T, Kawamura N, Ariga T, Kaneko H, Kondo N, Tsuge I, Yachie A, Sakiyama Y, Iwata T, Bessho F, Ohishi T, Joh K, Imai K, Kogawa K, Shinohara M, Fujieda M, Wakiguchi H, Pasic S, Abinun M, Ochs HD, Renner ED, Jansson A, Belohradsky BH, Metin A, Shimizu N, Mizutani S, Miyawaki T, Nonoyama S, Karasuyama H. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity. November 2006, 25 (5): 745–55. PMID 17088085. doi:10.1016/j.immuni.2006.09.009.
^ Watford WT, O'Shea JJ. Human tyk2 kinase deficiency: another primary immunodeficiency syndrome. Immunity. November 2006, 25 (5): 695–7. PMID 17098200. doi:10.1016/j.immuni.2006.10.007.
^ Minegishi Y, Karasuyama H. Hyperimmunoglobulin E syndrome and tyrosine kinase 2 deficiency. Curr Opin Allergy Clin Immunol. December 2007, 7 (6): 506–9. PMID 17989526. doi:10.1097/ACI.0b013e3282f1baea.
^ Uddin, S; Sher D A, Alsayed Y, Pons S, Colamonici O R, Fish E N, White M F, Platanias L C. Interaction of p59fyn with interferon-activated Jak kinases. Biochem. Biophys. Res. Commun. (United States). June 1997, 235 (1): 83–8. ISSN 0006-291X. PMID 9196040. doi:10.1006/bbrc.1997.6741.
^ Yetter, A; Uddin S, Krolewski J J, Jiao H, Yi T, Platanias L C. Association of the interferon-dependent tyrosine kinase Tyk-2 with the hematopoietic cell phosphatase. J. Biol. Chem. (United States). August 1995, 270 (31): 18179–82. ISSN 0021-9258. PMID 7629131. doi:10.1074/jbc.270.31.18179.
^ Richter, M F; Duménil G, Uzé G, Fellous M, Pellegrini S. Specific contribution of Tyk2 JH regions to the binding and the expression of the interferon alpha/beta receptor component IFNAR1. J. Biol. Chem. (United States). September 1998, 273 (38): 24723–9. ISSN 0021-9258. PMID 9733772. doi:10.1074/jbc.273.38.24723.
^ Kumar, K G Suresh; Varghese Bentley, Banerjee Anamika, Baker Darren P, Constantinescu Stefan N, Pellegrini Sandra, Fuchs Serge Y. Basal ubiquitin-independent internalization of interferon alpha receptor is prevented by Tyk2-mediated masking of a linear endocytic motif. J. Biol. Chem. (United States). July 2008, 283 (27): 18566–72. ISSN 0021-9258. PMC 2441555 . PMID 18474601. doi:10.1074/jbc.M800991200.
^ Adam, L; Bandyopadhyay D, Kumar R. Interferon-alpha signaling promotes nucleus-to-cytoplasmic redistribution of p95Vav, and formation of a multisubunit complex involving Vav, Ku80, and Tyk2. Biochem. Biophys. Res. Commun. (United States). January 2000, 267 (3): 692–6. ISSN 0006-291X. PMID 10673353. doi:10.1006/bbrc.1999.1978.
^ Usacheva, Anna; Tian Xinyong, Sandoval Raudel, Salvi Debra, Levy David, Colamonici Oscar R. The WD motif-containing protein RACK-1 functions as a scaffold protein within the type I IFN receptor-signaling complex. J. Immunol. (United States). September 2003, 171 (6): 2989–94. ISSN 0022-1767. PMID 12960323.

延伸阅读

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Partanen J, Mäkelä TP, Alitalo R; et al. Putative tyrosine kinases expressed in K-562 human leukemia cells.. Proc. Natl. Acad. Sci. U.S.A. 1991, 87 (22): 8913–7. PMC 55070 . PMID 2247464. doi:10.1073/pnas.87.22.8913.
Colamonici O, Yan H, Domanski P; et al. Direct binding to and tyrosine phosphorylation of the alpha subunit of the type I interferon receptor by p135tyk2 tyrosine kinase.. Mol. Cell. Biol. 1994, 14 (12): 8133–42. PMC 359352 . PMID 7526154.
Novak U, Harpur AG, Paradiso L; et al. Colony-stimulating factor 1-induced STAT1 and STAT3 activation is accompanied by phosphorylation of Tyk2 in macrophages and Tyk2 and JAK1 in fibroblasts.. Blood. 1995, 86 (8): 2948–56. PMID 7579387.
Domanski P, Yan H, Witte MM; et al. Homodimerization and intermolecular tyrosine phosphorylation of the Tyk-2 tyrosine kinase.. FEBS Lett. 1995, 374 (3): 317–22. PMID 7589562. doi:10.1016/0014-5793(95)01094-U.
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Maruyama K, Sugano S. Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides.. Gene. 1994, 138 (1-2): 171–4. PMID 8125298. doi:10.1016/0378-1119(94)90802-8.
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Gauzzi MC, Velazquez L, McKendry R; et al. Interferon-alpha-dependent activation of Tyk2 requires phosphorylation of positive regulatory tyrosines by another kinase.. J. Biol. Chem. 1996, 271 (34): 20494–500. PMID 8702790. doi:10.1074/jbc.271.34.20494.
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[1] 與酪氨酸激酶2相關的疾病；在維基數據上查看/編輯參考.

[2] 對酪氨酸激酶2起作用的藥物；在維基數據上查看/編輯參考.

[refGRCh38Ensembl-3] 3.0 ^3.1 ^3.2 GRCh38: Ensembl release 89: ENSG00000105397 - Ensembl, May 2017

[refGRCm38Ensembl-4] 4.0 ^4.1 ^4.2 GRCm38: Ensembl release 89: ENSMUSG00000032175 - Ensembl, May 2017

[5] Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.

[6] Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid2156206-7] Krolewski JJ, Lee R, Eddy R, Shows TB, Dalla-Favera R. Identification and chromosomal mapping of new human tyrosine kinase genes. Oncogene. March 1990, 5 (3): 277–82. PMID 2156206.

[entrez-8] 8.0 ^8.1 Entrez Gene: TYK2 tyrosine kinase 2. （原始内容存档于2019-06-14）.

[pmid9759489-9] 9.0 ^9.1 Stark GR, Kerr IM, Williams BR, Silverman RH, Schreiber RD. How cells respond to interferons. Annu. Rev. Biochem. 1998, 67 (1): 227–64. PMID 9759489. doi:10.1146/annurev.biochem.67.1.227.

[isbn0-19-859947-1-10] Nicola, Nicos. Guidebook to cytokines and their receptors. Oxford [Oxfordshire]: Oxford University Press. 1994. ISBN 0-19-859947-1.

[pmid14639467-11] Kubo M, Hanada T, Yoshimura A. Suppressors of cytokine signaling and immunity. Nat. Immunol. December 2003, 4 (12): 1169–76. PMID 14639467. doi:10.1038/ni1012.

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