参考:https://mp.weixin.qq.com/s/QLL6__bKHBrX-q82RiivMA
酪氨酸激酶(tyrosine kinase,TKs) 是细胞信号转导途径中的重要因子,参与调节细胞生长,分化和凋亡等一系列生理生化过程,酪氨酸激酶根据其结构可分为两大类:受体酪氨酸激酶和非受体酪氨酸激酶 。我简单代码查看了一下:
library(org.Hs.eg.db)
ids=toTable(org.Hs.egGENENAME)
head(ids)
all_kinase =ids[grepl('kinase',ids$gene_name),]
all_tyrosine_kinase =all_kinase[grepl('tyrosine',all_kinase$gene_name),]
nkt= all_tyrosine_kinase[grepl('non',all_tyrosine_kinase$gene_name),]
nkt
rkt= all_tyrosine_kinase[!grepl('non',all_tyrosine_kinase$gene_name),]
rkt
可以看到,非受体酪氨酸激酶 就6个,如下所示:
[1] "ABL proto-oncogene 1, non-receptor tyrosine kinase"
[2] "ABL proto-oncogene 2, non-receptor tyrosine kinase"
[3] "BMX non-receptor tyrosine kinase"
[4] "SRC proto-oncogene, non-receptor tyrosine kinase"
[5] "tyrosine kinase non receptor 1"
[6] "tyrosine kinase non receptor 2"
但是 受体型酪氨酸激酶(receptor tyrosine kinases,RTKs)就超级多:
[1] "ALK receptor tyrosine kinase"
[2] "AXL receptor tyrosine kinase"
[3] "BLK proto-oncogene, Src family tyrosine kinase"
[4] "Bruton tyrosine kinase"
[5] "discoidin domain receptor tyrosine kinase 1"
[6] "dual specificity tyrosine phosphorylation regulated kinase 1A"
[7] "erb-b2 receptor tyrosine kinase 2"
[8] "erb-b2 receptor tyrosine kinase 3"
[9] "erb-b2 receptor tyrosine kinase 4"
[10] "protein tyrosine kinase 2 beta"
[11] "FER tyrosine kinase"
[12] "FES proto-oncogene, tyrosine kinase"
[13] "FGR proto-oncogene, Src family tyrosine kinase"
[14] "fms related receptor tyrosine kinase 1"
[15] "fms related receptor tyrosine kinase 3"
[16] "fms related receptor tyrosine kinase 3 ligand"
[17] "fms related receptor tyrosine kinase 4"
[18] "fyn related Src family tyrosine kinase"
[19] "FYN proto-oncogene, Src family tyrosine kinase"
[20] "HCK proto-oncogene, Src family tyrosine kinase"
[21] "KIT proto-oncogene, receptor tyrosine kinase"
[22] "LCK proto-oncogene, Src family tyrosine kinase"
[23] "leukocyte receptor tyrosine kinase"
[24] "LYN proto-oncogene, Src family tyrosine kinase"
[25] "megakaryocyte-associated tyrosine kinase"
[26] "MET proto-oncogene, receptor tyrosine kinase"
[27] "muscle associated receptor tyrosine kinase"
[28] "neurotrophic receptor tyrosine kinase 1"
[29] "neurotrophic receptor tyrosine kinase 2"
[30] "neurotrophic receptor tyrosine kinase 3"
[31] "receptor tyrosine kinase like orphan receptor 1"
[32] "receptor tyrosine kinase like orphan receptor 2"
[33] "discoidin domain receptor tyrosine kinase 2"
[34] "protein tyrosine kinase 2"
[35] "protein tyrosine kinase 6"
[36] "protein tyrosine kinase 7 (inactive)"
[37] "ROS proto-oncogene 1, receptor tyrosine kinase"
[38] "receptor like tyrosine kinase"
[39] "src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristylation sites"
[40] "spleen associated tyrosine kinase"
[41] "tec protein tyrosine kinase"
[42] "TEK receptor tyrosine kinase"
[43] "tyrosine kinase with immunoglobulin like and EGF like domains 1"
[44] "TXK tyrosine kinase"
[45] "tyrosine kinase 2"
[46] "TYRO3 protein tyrosine kinase"
[47] "TYRO3P protein tyrosine kinase pseudogene"
[48] "YES proto-oncogene 1, Src family tyrosine kinase"
[49] "dual specificity tyrosine phosphorylation regulated kinase 3"
[50] "dual specificity tyrosine phosphorylation regulated kinase 2"
[51] "dual specificity tyrosine phosphorylation regulated kinase 4"
[52] "protein kinase, membrane associated tyrosine/threonine 1"
[53] "hepatocyte growth factor-regulated tyrosine kinase substrate"
[54] "dual specificity tyrosine phosphorylation regulated kinase 1B"
[55] "apoptosis associated tyrosine kinase"
[56] "MER proto-oncogene, tyrosine kinase"
[57] "lemur tyrosine kinase 2"
[58] "dual serine/threonine and tyrosine protein kinase"
[59] "inhibitor of Bruton tyrosine kinase"
[60] "serine/threonine/tyrosine kinase 1"
[61] "neuronal tyrosine-phosphorylated phosphoinositide-3-kinase adaptor 2"
[62] "lemur tyrosine kinase 3"
[63] "neuronal tyrosine phosphorylated phosphoinositide-3-kinase adaptor 1"
[64] "FER tyrosine kinase pseudogene 1"
[65] "inhibitor of Bruton tyrosine kinase pseudogene 1"
如果是要死记硬背这么多基因,肯定是累人,还好它们区分成为了几个家族,有一个很巧妙的背诵方法。我这里就不班门弄虎。
研究表明,在肿瘤组织中,酪氨酸激酶常被激活,继而激活下游的信号传导通路,促进细胞增殖、抑制细胞凋亡,促使肿瘤发展,由于酪氨酸激酶在肿瘤发生中的关键作用,因此酪氨酸激酶抑制剂(TKI)通过特异性阻断细胞增殖信号,成为了肿瘤治疗的重要靶向药物。
我们通常说的酪氨酸激酶抑制剂(TKI)主要是针对受体型酪氨酸激酶(receptor tyrosine kinases,RTKs),它们一般位于细胞膜上,能与相应的配体结合,并通过自磷酸化激活其酪氨酸激酶活性,包括:
但是ABL激酶是非受体的, Abl nonreceptor tyrosine kinase is activated by ligand-stimulated EGFR
2001年第一个BCR/ABL激酶抑制剂——伊马替尼,也是人类肿瘤肿瘤历史上第一个酪氨酸激酶抑制剂(TKI)。伊马替尼的出现具有划时代的意义,将CML的十年生存率从以前的不到50%,增加到了现在的90%左右。后续随着肿瘤细胞对一代ABL激酶耐药性的出现,第二代,第三代ABL激酶抑制剂也陆续应运而生。
第一代TKIs多为单靶点,代表药物有伊马替尼、吉非替尼、厄洛替尼、埃克替尼、索拉非尼、舒尼替尼、克唑替尼等。
由于第一代TKIs耐药性的出现,以及受激酶通路交叉和代偿机制的影响,酪氨酸激酶抑制剂的研发向纵深发展。于是第二代TKIs的靶点更为广谱,代表药物有拉帕替尼、阿法替尼、达克替尼、阿西替尼、色瑞替尼等。其中
相较于前两代,第三代TKIs的选择性更高,临床效果更佳且毒性更小,代表药物有奥希替尼、劳拉替尼、来那替尼等。
除了上述已经用于临床治疗的药物,目前处于临床(前)研究阶段的酪氨酸激酶抑制剂包括布加替尼(Brigatinib)、恩沙替尼 (Ensartinib)、AZD8186、GSK2636771、LOXO-292等。
参考:https://mp.weixin.qq.com/s/4xNaeedJwPHumB8blW28_A
RTKs的激活机制:RTKs配体(如EGF)在胞外与受体(如EGFR)结合并引起构象变化,导致受体(如EGFR)二聚化(dimerization)形成同源或异源二聚体,在二聚体内彼此相互磷酸化胞内段酪氨酸残基,激活受体(如EGFR)本身的酪氨酸激酶活性。
参考:https://mp.weixin.qq.com/s/4xNaeedJwPHumB8blW28_A
BCR/ABL激酶(兰色)有两个结合位点,一个结合ATP(黄色),一个结合底物(粉色),在两个位点结合后,磷酸基团(绿色)从ATP转移到底物上,使底物酪氨酸残基磷酸化。酪氨酸激酶抑制剂(Tyrosine Kinase Inhibitor,TKI)可以选择性地阻断ATP与BCR/ABL激酶结合位点,有效地抑制BCR/ABL激酶底物中酪氨酸残基的磷酸化,使该酶失活,进而阻止了一系列的信号传导,引起BCR/ABL阳性的细胞凋亡。
代码如下所示:
library(SeuratData) #加载seurat数据集
getOption('timeout')
options(timeout=10000)
#InstallData("pbmc3k")
data("pbmc3k")
sce <- pbmc3k.final
library(Seurat)
ids=toTable(org.Hs.egSYMBOL)
head(ids)
cg=merge(ids,all_tyrosine_kinase,by='gene_id')[,2]
library(stringr)
library(ggplot2)
p <- DotPlot(sce, features = cg,
assay='RNA' ) +theme(axis.text.x = element_text(angle = 90))
p
th=theme(axis.text.x = element_text(angle = 45,
vjust = 0.5, hjust=0.5))
p+th
如下所示:
激酶在血液的不同免疫细胞是否有表达量差异
蛮有意思的!