酪氨酸激酶2
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非受體酪氨酸激酶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
酪氨酸激酶2是TYK2基因編碼的酪氨酸激酶中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炎症中起關鍵作用[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。白細胞介素、干擾素和促紅細胞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和酪氨酸激酶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(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激活必要組件[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(OSM)、睫狀神經營養因子、心肌營養素1、心肌營養素樣細胞因子因子以及LIF,Tyk2都具有信號傳導作用。近來由發現了IL-12和IL-23在激活Tyk2的過程中使用了相同的配體與受體亞基。
IL-10是一個關鍵的抗炎性細胞因子,IL-10基因敲除的小鼠會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]。
炎症上的機制
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(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(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(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(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(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(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
酪氨酸激酶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.
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