TISIDB

Summary
Symbol	ITK
Name	IL2-inducible T-cell kinase
Aliases	LYK; LPFS1; IL-2-inducible T cell kinase; IL-2-inducible T-cell kinase; T-cell-specific kinase; homolog of m ......
Chromosomal Location	5q31-q32
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Basic function annotation. > Subcellular Location, Domain and Function > Gene Ontology > KEGG and Reactome Pathway

> Subcellular Location, Domain and Function [ TOP ]
Subcellular Location	Cytoplasm Nucleus Note=Localizes in the vicinity of cell surface receptors in the plasma membrane after receptor stimulation.
Domain	PF00779 BTK motif PF00169 PH domain PF07714 Protein tyrosine kinase PF00017 SH2 domain PF00018 SH3 domain
Function	Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. When antigen presenting cells (APC) activate T-cell receptor (TCR), a series of phosphorylation lead to the recruitment of ITK to the cell membrane, in the vicinity of the stimulated TCR receptor, where it is phosphorylated by LCK. Phosphorylation leads to ITK autophosphorylation and full activation. Once activated, phosphorylates PLCG1, leading to the activation of this lipase and subsequent cleavage of its substrates. In turn, the endoplasmic reticulum releases calcium in the cytoplasm and the nuclear activator of activated T-cells (NFAT) translocates into the nucleus to perform its transcriptional duty. Phosphorylates 2 essential adapter proteins: the linker for activation of T-cells/LAT protein and LCP2. Then, a large number of signaling molecules such as VAV1 are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation (PubMed:12186560, PubMed:12682224, PubMed:21725281). Phosphorylates TBX21 at 'Tyr-530' and mediates its interaction with GATA3 (By similarity).

> Gene Ontology [ TOP ]
Biological Process	GO:0001865 NK T cell differentiation GO:0002250 adaptive immune response GO:0002429 immune response-activating cell surface receptor signaling pathway GO:0002521 leukocyte differentiation GO:0002757 immune response-activating signal transduction GO:0002764 immune response-regulating signaling pathway GO:0002768 immune response-regulating cell surface receptor signaling pathway GO:0006968 cellular defense response GO:0007159 leukocyte cell-cell adhesion GO:0007202 activation of phospholipase C activity GO:0010517 regulation of phospholipase activity GO:0010518 positive regulation of phospholipase activity GO:0010863 positive regulation of phospholipase C activity GO:0018108 peptidyl-tyrosine phosphorylation GO:0018212 peptidyl-tyrosine modification GO:0030098 lymphocyte differentiation GO:0030217 T cell differentiation GO:0032609 interferon-gamma production GO:0032633 interleukin-4 production GO:0038083 peptidyl-tyrosine autophosphorylation GO:0038093 Fc receptor signaling pathway GO:0038095 Fc-epsilon receptor signaling pathway GO:0042110 T cell activation GO:0046631 alpha-beta T cell activation GO:0046632 alpha-beta T cell differentiation GO:0046777 protein autophosphorylation GO:0050851 antigen receptor-mediated signaling pathway GO:0050852 T cell receptor signaling pathway GO:0060191 regulation of lipase activity GO:0060193 positive regulation of lipase activity GO:0070486 leukocyte aggregation GO:0070489 T cell aggregation GO:0071593 lymphocyte aggregation GO:1900274 regulation of phospholipase C activity
Molecular Function	GO:0004713 protein tyrosine kinase activity GO:0004715 non-membrane spanning protein tyrosine kinase activity
Cellular Component	GO:0009898 cytoplasmic side of plasma membrane GO:0019897 extrinsic component of plasma membrane GO:0019898 extrinsic component of membrane GO:0031234 extrinsic component of cytoplasmic side of plasma membrane GO:0098552 side of membrane GO:0098562 cytoplasmic side of membrane

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa04062 Chemokine signaling pathway hsa04660 T cell receptor signaling pathway hsa04670 Leukocyte transendothelial migration
Reactome	R-HSA-1280218: Adaptive Immune System R-HSA-2871809: FCERI mediated Ca+2 mobilization R-HSA-2454202: Fc epsilon receptor (FCERI) signaling R-HSA-202433: Generation of second messenger molecules R-HSA-168256: Immune System R-HSA-168249: Innate Immune System R-HSA-202403: TCR signaling

Summary
Symbol	ITK
Name	IL2-inducible T-cell kinase
Aliases	LYK; LPFS1; IL-2-inducible T cell kinase; IL-2-inducible T-cell kinase; T-cell-specific kinase; homolog of m ......
Chromosomal Location	5q31-q32
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between ITK and anti-tumor immunity. The specific mechanism were also collected if the literature reports that a gene specifically promotes or inhibits the infiltration or function of T/NK cells.

> Text Mining

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Literatures describing the relation between ITK and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
28714866	Chronic Lymphocytic Leukemia	Inhibit immunity	Peripheral blood mononuclear cells from chronic lymphocytic leukemia (CLL) patients on clinical trials of ibrutinib (BTK/ITK inhibitor; n = 19) or acalabrutinib (selective BTK inhibitor; n = 13) were collected serially. Ibrutinib markedly increased CD4+ and CD8+ T cell numbers in CLL patients. This effect was more prominent in effector/effector memory subsets and was not observed with acalabrutinib. Ex vivo studies demonstrated that this may be due to diminished activation-induced cell death through ITK inhibition. Both agents reduced expression of the immunosuppressive molecules CD200 and BTLA as well as IL-10 production by CLL cells. PD-1 and CTLA-4 expression was significantly markedly reduced in T cells by both agents.

Summary
Symbol	ITK
Name	IL2-inducible T-cell kinase
Aliases	LYK; LPFS1; IL-2-inducible T cell kinase; IL-2-inducible T-cell kinase; T-cell-specific kinase; homolog of m ......
Chromosomal Location	5q31-q32
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	High-throughput screening data (e.g. CRISPR-Cas9, shRNA and RNAi) for T cell-mediated killing. Genetic screen techniques can identify mechanisms of tumor cell resistance (e.g., PTPN2) and sensitivity (e.g., APLNR) to killing by cytotoxic T cells, the central effectors of anti-tumor immunity. After comprehensively searching, eight groups of screening data sets were collected in the current database. In this tab, users can check whether their selected genes cause resistance or increase sensitivity to T cell-mediated killing in various data sets.

> High-throughput Screening

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Statistical results of ITK in screening data sets for detecting immune reponses.

PMID	Screening System	Cancer Type	Cell Line	Data Set	Statistical Results	Relation to immunity
29301958	CRISPR-Cas9	melanoma	B16F10	Pmel-1 T cell	NA/NS	NA/NS
29301958	CRISPR-Cas9	melanoma	B16F10	OT-1 T cell	NA/NS	NA/NS
28783722	CRISPR-Cas9	melanoma	Mel624	2CT-CRISPR	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX+Anti-PD1	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX	NA/NS	NA/NS
25691366	RNAi	Breast cancer	MCF7	Luc-CTL assay	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Primary screen	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Secondary screen	NA/NS	NA/NS

Summary
Symbol	ITK
Name	IL2-inducible T-cell kinase
Aliases	LYK; LPFS1; IL-2-inducible T cell kinase; IL-2-inducible T-cell kinase; T-cell-specific kinase; homolog of m ......
Chromosomal Location	5q31-q32
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Transcriptomic and genomic profiling of pre-treated tumor biopsies from responders and non-responders to immunotherapy. These data were used to identify signatures and mechanisms of response to checkpoint blockade (e.g., anti-PDL1 and anti-PD1). One example is that mutations in the gene PBRM1 benefit clinical survival of patients with clear cell renal cell carcinoma. After comprehensively searching, we collected 5 and 6 of transcriptomic and genomic data sets, respectively. In this tab, users can check whether their selected genes have significant difference of expression or mutation between responders and non-responders in various data sets. > Expression difference between responders and non-responders > Mutation difference between responders and non-responders

> Expression difference between responders and non-responders

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Points in the above scatter plot represent the expression difference of ITK in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	Log2 (Fold Change)	P value
1	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	14	12	-0.027	0.947
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	0.743	0.326
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	-0.593	0.359
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0.109	0.811
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0.166	0.91
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0.039	0.983
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	1.253	0.0669
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	1.726	0.142
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	0.819	0.504
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	1.571	0.0393
11	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	2	0	0	1
12	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	2	8	1.686	0.148
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	-0.222	0.363

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of ITK in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	% Mut/Res	% Mut/NRes	% Diff (R vs NR)	Pval
1	25765070	Non-small cell lung cancer (NSCLC)	all	Anti-PD-1 (pembrolizumab)	14	17	7.1	0	7.1	0.452
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	10	0	10	1
3	25765070	Non-small cell lung cancer (NSCLC)	non-smoking	Anti-PD-1 (pembrolizumab)	4	14	0	0	0	1
4	26359337	Melanoma	all	Anti-CTLA-4 (ipilimumab)	27	73	7.4	2.7	4.7	0.294
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	7.1	-7.1	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	7.4	1.7	5.7	0.231
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	0	0	0	1
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	0	0	0	1
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	0	0	0	1
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	11.1	0	11.1	0.36
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0	0	0	1
12	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	25	0	25	0.364
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	2.6	7.4	-4.8	0.565
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	4.5	7.7	-3.2	1
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	0	7.1	-7.1	0.467
16	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	11	13	0	0	0	1
17	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	6	1	0	0	0	1
18	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	5	12	0	0	0	1

Summary
Symbol	ITK
Name	IL2-inducible T-cell kinase
Aliases	LYK; LPFS1; IL-2-inducible T cell kinase; IL-2-inducible T-cell kinase; T-cell-specific kinase; homolog of m ......
Chromosomal Location	5q31-q32
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of ITK. The immune-related signatures of 28 TIL types from Charoentong's study, which can be viewed in the download page. For each cancer type, the relative abundance of TILs were inferred by using gene set variation analysis (GSVA) based on gene expression profile. In this tab, users can examine which kinds of TILs might be regulated by the current gene.

> Lymphocyte [ TOP ]

Summary
Symbol	ITK
Name	IL2-inducible T-cell kinase
Aliases	LYK; LPFS1; IL-2-inducible T cell kinase; IL-2-inducible T-cell kinase; T-cell-specific kinase; homolog of m ......
Chromosomal Location	5q31-q32
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of ITK. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by ITK. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	ITK
Name	IL2-inducible T-cell kinase
Aliases	LYK; LPFS1; IL-2-inducible T cell kinase; IL-2-inducible T-cell kinase; T-cell-specific kinase; homolog of m ......
Chromosomal Location	5q31-q32
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of ITK. In this tab, users can examine which chemokines (or receptors) might be regulated by the current gene. > Chemokine > Receptor

> Chemokine [ TOP ]

> Receptor [ TOP ]

Summary
Symbol	ITK
Name	IL2-inducible T-cell kinase
Aliases	LYK; LPFS1; IL-2-inducible T cell kinase; IL-2-inducible T-cell kinase; T-cell-specific kinase; homolog of m ......
Chromosomal Location	5q31-q32
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of ITK expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	ITK
Name	IL2-inducible T-cell kinase
Aliases	LYK; LPFS1; IL-2-inducible T cell kinase; IL-2-inducible T-cell kinase; T-cell-specific kinase; homolog of m ......
Chromosomal Location	5q31-q32
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between ITK and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	ITK
Name	IL2-inducible T-cell kinase
Aliases	LYK; LPFS1; IL-2-inducible T cell kinase; IL-2-inducible T-cell kinase; T-cell-specific kinase; homolog of m ......
Chromosomal Location	5q31-q32
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting ITK collected from DrugBank database.

> Drugs from DrugBank database

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Details on drugs targeting ITK.

ID	Name	Drug Type	Targets	#Targets
DB02010	Staurosporine	Small Molecule	CDK2, CHRM1, CSK, GSK3B, ITK, LCK, MAPKAPK2, PDPK1, PIK3CG, PIM1, ......	13
DB06589	Pazopanib	Small Molecule	FGF1, FGFR3, FLT1, FLT4, ITK, KDR, KIT, PDGFRA, PDGFRB, SH2B3	10

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