reference resources: https://mp.weixin.qq.com/s/QLL6__bKHBrX-q82RiivMA
Tyrosine kinase (TKs) is an important factor in cell signal transduction pathway. It is involved in regulating a series of physiological and biochemical processes such as cell growth, differentiation and apoptosis. According to its structure, tyrosine kinase can be divided into two categories: receptor tyrosine kinase and non receptor tyrosine kinase. I simply checked the code:
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
It can be seen that there are only 6 non receptor tyrosine kinases, as shown below:
[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"
However, there are many receptor tyrosine kinases (RTKs):
[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"
If you want to memorize so many genes by rote, it must be tiring. Fortunately, they are divided into several families, and there is a very clever recitation method. I don't get tigers here.
Studies have shown that in tumor tissues, tyrosine kinase is often activated, and then activates the downstream signal transduction pathway to promote cell proliferation, inhibit cell apoptosis and promote tumor development. Due to the key role of tyrosine kinase in tumorigenesis, tyrosine kinase inhibitor (TKI) specifically blocks cell proliferation signals, It has become an important targeted drug for tumor therapy.
The tyrosine kinase inhibitors (TKI s) we usually talk about are mainly targeted at receptor tyrosine kinases (RTKs), which are generally located on the cell membrane, can bind to corresponding ligands and activate their tyrosine kinase activity through autophosphorylation, including:
- Vascular endothelial growth factor receptor (VEGFR)
- Platelet growth factor receptor (PDGFR)
- Epidermal growth factor receptor (EGFR), ErbB-1, HER1
- Human epidermal growth factor receptor-2 (HER-2), ERBB2
- Fibroblast growth factor receptor (FGFR);
ABL nonreceptor tyrosine kinase is activated by ligand stimulated EGFR
Imatinib, the first BCR/ABL kinase inhibitor in 2001, is also the first tyrosine kinase inhibitor (TKI) in human tumor history. The emergence of imatinib has epoch-making significance, increasing the ten-year survival rate of CML from less than 50% in the past to about 90% now. Subsequently, with the emergence of drug resistance of tumor cells to the first generation of ABL kinase, the second and third generation of ABL kinase inhibitors also came into being.
Three times
The first generation TKIs are mostly single target, and the representative drugs include imatinib, gefitinib, erlotinib, ektinib, sorafenib, sunitinib, kezotinib, etc.
Due to the emergence of drug resistance of the first generation TKIs and the influence of kinase pathway crossover and compensation mechanism, the research and development of tyrosine kinase inhibitors has developed in depth. Therefore, the target of the second generation TKIs is more broad-spectrum, and the representative drugs are lapatinib, afatinib, daktinib, asitinib, seretinib, etc. among
- Lapatinib, afatinib and dactinib could inhibit the expression of EGFR mutation and T790M drug resistance mutation at the same time;
- Seretinib can also inhibit ALK gene, which is used to treat lung cancer patients with ALK fusion mutation
Compared with the previous two generations, the third generation TKIs has higher selectivity, better clinical effect and less toxicity. The representative drugs include oshitinib, laratinib, lenatinib, etc.
In addition to the above drugs that have been used in clinical treatment, tyrosine kinase inhibitors currently in the clinical (pre) research stage include bugatinib, ensartinib, AZD8186, GSK2636771, LOXO-292, etc.
Activation mechanism of RTKs
reference resources: https://mp.weixin.qq.com/s/4xNaeedJwPHumB8blW28_A
Activation mechanism of RTKs: RTKs ligands (e.g. EGF) bind to receptors (e.g. EGFR) outside the cell and cause conformational changes, resulting in dimerization of receptors (e.g. EGFR) to form homologous or heterodimers, mutual phosphorylation of intracellular tyrosine residues in dimers, and activation of tyrosine kinase activity of receptors (e.g. EGFR).
How do kinase inhibitors play an anti-tumor role?
reference resources: https://mp.weixin.qq.com/s/4xNaeedJwPHumB8blW28_A
BCR/ABL kinase (blue) has two binding sites, one binding ATP (yellow) and one binding substrate (pink). After binding at the two sites, the phosphate group (green) is transferred from ATP to the substrate to phosphorylate the tyrosine residue of the substrate. Tyrosine Kinase Inhibitor (TKI) can selectively block the binding site between ATP and BCR/ABL kinase, effectively inhibit the phosphorylation of tyrosine residues in BCR/ABL kinase substrate, inactivate the enzyme, prevent a series of signal transduction and cause BCR/ABL positive cell apoptosis.
To see if there are differences in the expression of these kinases in different immune cells in the blood
The code is as follows:
library(SeuratData) #Load the seurat dataset
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
As follows:
Is there any difference in the expression of kinase in different immune cells of blood
Very interesting!