酪胺酸激酶2

酪胺酸激酶2
已知的結構
PDB	直系同源搜尋: 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
別名	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、第1型糖尿病、銀屑病、susceptibility to infection due to TYK2 deficiency
為以下藥物的標靶
	魯索利替尼
基因位置（人類）
染色體	19號染色體
終止	10,380,572 bp
基因位置（小鼠）
染色體	小鼠9號染色體
終止	21,042,539 bp
RNA表現模式
	查閱更多表現資料
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; • 血漿蛋白結合; • protein tyrosine kinase activity; • ATP結合; • non-membrane spanning protein tyrosine kinase activity;
細胞組分	• 細胞質; • 細胞質基質; • 膜; • extrinsic component of cytoplasmic side of plasma membrane; • 外排體; • 細胞骨架; • 細胞核;
生物學過程	• 細胞分化; • 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; • 細胞遷移; • 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
	維基資料
檢視/編輯人類	檢視/編輯小鼠

非受體酪胺酸激酶2（英語：Non-receptor tyrosine-protein kinase，TYK2）是人類基因組中TYK2基因所編碼的酶^[7]^[8]。

TYK2是JAK家族中第一個被報導的（該家族的其它成員有JAK1、JAK2和JAK3）^[9]，與干擾素α、IL-6、IL-10和IL-12的信號相關。

功能

酪胺酸激酶2是TYK2基因編碼的酪胺酸激酶中JAK激酶家族（JAKs）的一個成員蛋白。該蛋白與I型或II型細胞因子受體的胞質結構域結合，並通過磷酸化受體亞基來傳遞細胞因子的信號。該酶參與干擾素α和β產生的信號通路，因此也可能在抗病毒免疫中扮演一個角色^[8]。

細胞因子通過調節免疫細胞以及其它系統的細胞的存活、增殖、分化以及功能在免疫與發炎中起關鍵作用^[10]。因此，以細胞因子及其受體為靶標是治療這類疾病的有效手段。白血球介素、干擾素和促紅血球生成素等細胞因子正是通過I型和II型細胞因子受體與JAK家族的激酶結合來傳遞胞內信號。^[11]

哺乳動物的JAK激酶家族擁有四個成員：JAK1、JAK2、JAK3和酪胺酸激酶2（TYK2）^[9]。Jak激酶和細胞因子信號之間關係的第一次闡明是在篩選I型干擾素（英語：interferon type I）（IFN-1）信號相關基因時，鑑別出Tyk2是細胞因子受體進行一系列活化必要組件^[12]。而與早先在小鼠模型分析的基礎上鑑定出的Tyk2對IL-12與I型干擾素信號的介導相比，Tyk2在人類基因組中的功能更為廣泛和深刻。TYK2缺陷已在人類細胞中比在小鼠細胞的影響更大，在干擾素α和β以及IL-12之外，Tyk2還對IL-23、IL-10以及IL-6信號的轉導起重要作用。因此，對於與gp-130受體鏈相結合的IL-6類細胞因子，包括IL-6、IL-11、IL-27、IL-31、制瘤素（英語：MOncostatin M）（OSM）、睫狀神經營養因子（英語：ciliary neurotrophic factor）、心肌營養素1（英語：cardiotrophin 1）、心肌營養素樣細胞因子因子（英語：CLCF1）以及LIF，Tyk2都具有信號傳導作用。近來由發現了IL-12和IL-23在活化Tyk2的過程中使用了相同的配體與受體亞基。

IL-10是一個關鍵的抗發炎性細胞因子，IL-10基因剔除的小鼠會遭受致命的全身性自體免疫性疾病。Tyk2由IL-10活化它的缺乏會影響細胞生成和響應IL-10的能力^[13]。在一般生理條件下，免疫細胞會受到許多種細胞因子的調節作用。現在已經清楚的是，這些不同的細胞因子信號在通過JAK–STAT信號通路時，會發生相互串擾^[14]。

發炎上的機制

目前普遍認為動脈粥樣硬化肇因於發炎現象中的分子與細胞變化^[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（英語：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（英語：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（英語：glycoprotein 130）（glycoprotein 130，gp-130）和酪胺酸激酶（JAK1、JAK2和Tyk2）^[16]。

在慢性氣喘患者的肺中，細胞因子白細胞介素4（Interleukin 4，IL-4）和白細胞介素13（英語：Interleukin 13）（Interleukin 13，IL-13）的濃度會升高。經由IL-4/IL-13複合物的資訊途徑被認為是由白細胞介素6受體（英語：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醣（Lipopolysaccharide，LPS）的刺激而釋放出一氧化氮。對於這LPS資訊傳送的分子機制，進一步的研究發現，Tyk2和IFN-β的缺失會阻抗脂多醣誘導內毒素性休克（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（英語：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關。^[23]^[24]^[25]

交互作用

酪胺酸激酶2已知能與FYN^[26]、PTPN6^[27]、IFNAR1^[28]^[29]、Ku80^[30]以及GNB2L1^[31]發生相互作用。

參考文獻

^ 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. （原始內容存檔於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. （原始內容存檔於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. （原始內容存檔於2019-06-14）. 引用錯誤：帶有name屬性「pmid11070174」的<ref>標籤用不同內容定義了多次
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^ Shaw MH, Boyartchuk V, Wong S, Karaghiosoff M, Ragimbeau J, Pellegrini S, Muller M, Dietrich WF, Yap GS. A natural mutation in the Tyk2 pseudokinase domain underlies altered susceptibility of B10.Q/J mice to infection and autoimmunity. Proc. Natl. Acad. Sci. U.S.A. September 2003, 100 (20): 11594–9. PMC 208803  . PMID 14500783. doi:10.1073/pnas.1930781100.
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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.

延伸閱讀

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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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[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. （原始內容存檔於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.

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