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。
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(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(OSM)、睫状神经营养因子、心肌营养素1、心肌营养素样细胞因子因子以及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]。
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(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]。
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关。[23][24][25]
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。
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