TISIDB

Summary
Symbol	TBK1
Name	TANK-binding kinase 1
Aliases	NAK; T2K; NF-kB-activating kinase; NF-kappa-B-activating kinase; Serine/threonine-protein kinase TBK1
Chromosomal Location	12q14.2
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 Note=Upon mitogen stimulation or triggering of the immune system, TBK1 is recruited to the exocyst by EXOC2.
Domain	PF00069 Protein kinase domain
Function	Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents. Following activation of toll-like receptors by viral or bacterial components, associates with TRAF3 and TANK and phosphorylates interferon regulatory factors (IRFs) IRF3 and IRF7 as well as DDX3X. This activity allows subsequent homodimerization and nuclear translocation of the IRFs leading to transcriptional activation of pro-inflammatory and antiviral genes including IFNA and IFNB. In order to establish such an antiviral state, TBK1 form several different complexes whose composition depends on the type of cell and cellular stimuli. Thus, several scaffolding molecules including FADD, TRADD, MAVS, AZI2, TANK or TBKBP1/SINTBAD can be recruited to the TBK1-containing-complexes. Under particular conditions, functions as a NF-kappa-B effector by phosphorylating NF-kappa-B inhibitor alpha/NFKBIA, IKBKB or RELA to translocate NF-Kappa-B to the nucleus. Restricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/Optineurin on 'Ser-177', thus enhancing LC3 binding affinity and antibacterial autophagy (PubMed:21617041). Phosphorylates SMCR8 component of the C9orf72-SMCR8 complex, promoting autophagosome maturation (PubMed:27103069). Phosphorylates and activates AKT1 (PubMed:21464307). Seems to play a role in energy balance regulation by sustaining a state of chronic, low-grade inflammation in obesity, wich leads to a negative impact on insulin sensitivity. Attenuates retroviral budding by phosphorylating the endosomal sorting complex required for transport-I (ESCRT-I) subunit VPS37C (PubMed:21270402). Phosphorylates Borna disease virus (BDV) P protein (PubMed:16155125).

> Gene Ontology [ TOP ]
Biological Process	GO:0001818 negative regulation of cytokine production GO:0001819 positive regulation of cytokine production GO:0002218 activation of innate immune response GO:0002221 pattern recognition receptor signaling pathway GO:0002224 toll-like receptor signaling pathway GO:0002756 MyD88-independent toll-like receptor signaling pathway GO:0002757 immune response-activating signal transduction GO:0002758 innate immune response-activating signal transduction GO:0002764 immune response-regulating signaling pathway GO:0002831 regulation of response to biotic stimulus GO:0002833 positive regulation of response to biotic stimulus GO:0006914 autophagy GO:0007249 I-kappaB kinase/NF-kappaB signaling GO:0009615 response to virus GO:0010506 regulation of autophagy GO:0010508 positive regulation of autophagy GO:0016236 macroautophagy GO:0016239 positive regulation of macroautophagy GO:0016241 regulation of macroautophagy GO:0018105 peptidyl-serine phosphorylation GO:0018209 peptidyl-serine modification GO:0031349 positive regulation of defense response GO:0032103 positive regulation of response to external stimulus GO:0032479 regulation of type I interferon production GO:0032480 negative regulation of type I interferon production GO:0032481 positive regulation of type I interferon production GO:0032606 type I interferon production GO:0032607 interferon-alpha production GO:0032608 interferon-beta production GO:0032647 regulation of interferon-alpha production GO:0032648 regulation of interferon-beta production GO:0032727 positive regulation of interferon-alpha production GO:0032728 positive regulation of interferon-beta production GO:0032943 mononuclear cell proliferation GO:0033135 regulation of peptidyl-serine phosphorylation GO:0033138 positive regulation of peptidyl-serine phosphorylation GO:0035666 TRIF-dependent toll-like receptor signaling pathway GO:0042035 regulation of cytokine biosynthetic process GO:0042089 cytokine biosynthetic process GO:0042107 cytokine metabolic process GO:0042108 positive regulation of cytokine biosynthetic process GO:0042742 defense response to bacterium GO:0043122 regulation of I-kappaB kinase/NF-kappaB signaling GO:0043123 positive regulation of I-kappaB kinase/NF-kappaB signaling GO:0043900 regulation of multi-organism process GO:0043902 positive regulation of multi-organism process GO:0044565 dendritic cell proliferation GO:0045088 regulation of innate immune response GO:0045089 positive regulation of innate immune response GO:0045350 interferon-beta biosynthetic process GO:0045351 type I interferon biosynthetic process GO:0045357 regulation of interferon-beta biosynthetic process GO:0045359 positive regulation of interferon-beta biosynthetic process GO:0046651 lymphocyte proliferation GO:0050830 defense response to Gram-positive bacterium GO:0051607 defense response to virus GO:0070661 leukocyte proliferation GO:0070997 neuron death GO:0098542 defense response to other organism GO:0098792 xenophagy GO:1901214 regulation of neuron death GO:1904415 regulation of xenophagy GO:1904417 positive regulation of xenophagy
Molecular Function	GO:0004674 protein serine/threonine kinase activity GO:0051219 phosphoprotein binding
Cellular Component	GO:0010008 endosome membrane GO:0044440 endosomal part

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa04014 Ras signaling pathway hsa04620 Toll-like receptor signaling pathway hsa04621 NOD-like receptor signaling pathway hsa04622 RIG-I-like receptor signaling pathway hsa04623 Cytosolic DNA-sensing pathway
Reactome	R-HSA-166054: Activated TLR4 signalling R-HSA-936964: Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon R-HSA-1834949: Cytosolic sensors of pathogen-associated DNA R-HSA-1606341: IRF3 mediated activation of type 1 IFN R-HSA-3270619: IRF3-mediated induction of type I IFN R-HSA-168256: Immune System R-HSA-168249: Innate Immune System R-HSA-166166: MyD88-independent TLR3/TLR4 cascade R-HSA-936440: Negative regulators of RIG-I/MDA5 signaling R-HSA-168928: RIG-I/MDA5 mediated induction of IFN-alpha/beta pathways R-HSA-3134975: Regulation of innate immune responses to cytosolic DNA R-HSA-3249367: STAT6-mediated induction of chemokines R-HSA-1834941: STING mediated induction of host immune responses R-HSA-918233: TRAF3-dependent IRF activation pathway R-HSA-933541: TRAF6 mediated IRF7 activation R-HSA-937061: TRIF-mediated TLR3/TLR4 signaling R-HSA-168164: Toll Like Receptor 3 (TLR3) Cascade R-HSA-166016: Toll Like Receptor 4 (TLR4) Cascade R-HSA-168898: Toll-Like Receptors Cascades R-HSA-1606322: ZBP1(DAI) mediated induction of type I IFNs

> KEGG and Reactome Pathway

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KEGG

hsa04014 Ras signaling pathway
hsa04620 Toll-like receptor signaling pathway
hsa04621 NOD-like receptor signaling pathway
hsa04622 RIG-I-like receptor signaling pathway
hsa04623 Cytosolic DNA-sensing pathway

Reactome

R-HSA-166054: Activated TLR4 signalling
R-HSA-936964: Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon
R-HSA-1834949: Cytosolic sensors of pathogen-associated DNA
R-HSA-1606341: IRF3 mediated activation of type 1 IFN
R-HSA-3270619: IRF3-mediated induction of type I IFN
R-HSA-168256: Immune System
R-HSA-168249: Innate Immune System
R-HSA-166166: MyD88-independent TLR3/TLR4 cascade
R-HSA-936440: Negative regulators of RIG-I/MDA5 signaling
R-HSA-168928: RIG-I/MDA5 mediated induction of IFN-alpha/beta pathways
R-HSA-3134975: Regulation of innate immune responses to cytosolic DNA
R-HSA-3249367: STAT6-mediated induction of chemokines
R-HSA-1834941: STING mediated induction of host immune responses
R-HSA-918233: TRAF3-dependent IRF activation pathway
R-HSA-933541: TRAF6 mediated IRF7 activation
R-HSA-937061: TRIF-mediated TLR3/TLR4 signaling
R-HSA-168164: Toll Like Receptor 3 (TLR3) Cascade
R-HSA-166016: Toll Like Receptor 4 (TLR4) Cascade
R-HSA-168898: Toll-Like Receptors Cascades
R-HSA-1606322: ZBP1(DAI) mediated induction of type I IFNs

Summary
Symbol	TBK1
Name	TANK-binding kinase 1
Aliases	NAK; T2K; NF-kB-activating kinase; NF-kappa-B-activating kinase; Serine/threonine-protein kinase TBK1
Chromosomal Location	12q14.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between TBK1 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 TBK1 and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
28356390	Melanoma	Inhibit immunity	DC-specific deletion of Tbk1 causes T cell activation and autoimmune symptoms and also enhances antitumor immunity in animal models of cancer immunotherapy. The TBK1-deficient DCs have up-regulated expression of co-stimulatory molecules and increased T cell-priming activity.
24449872	Breast Carcinoma	Inhibit immunity; Resistant to immunotherapy	Here, we report that an important innate immune response kinase, the IκB kinase-related TANK-binding kinase 1 (TBK1), is a crucial determinant of resistance to tamoxifen therapies. We show that TBK1 increases ERα transcriptional activity through phosphorylation modification of ERα at the Ser-305 site. Notably, patients with tumors highly expressing TBK1 respond poorly to tamoxifen treatment and show high potential for relapse.
29721392	Hepatocellular Carcinoma	Resistant to immunotherapy	Inhibitor for TBK1 but not NF-κB suppressed poly (I:C)-inspired migration and invasion, which was further supported by using TBK1 deficient (Tbk1-/- ) cells. Our data suggest that bufalin can suppress the metastasis of HCC cells in poly (I:C) therapy by impairing TBK1 activation, indicating that bufalin may be used in combination with poly (I:C) therapy in HCC treatment for the sake of reversing poly (I:C)-triggered metastasis of HCC cells.

Summary
Symbol	TBK1
Name	TANK-binding kinase 1
Aliases	NAK; T2K; NF-kB-activating kinase; NF-kappa-B-activating kinase; Serine/threonine-protein kinase TBK1
Chromosomal Location	12q14.2
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 TBK1 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	logFC: -2.58; FDR: 0.04630	Resistant to T cell-mediated killing
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	STARS Score: 6.07; FDR: 0.000	Resistant to T cell-mediated killing
28723893	CRISPR-Cas9	melanoma	B16	GVAX	STARS Score: 4.35; FDR: 0.013	Resistant to T cell-mediated killing
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	TBK1
Name	TANK-binding kinase 1
Aliases	NAK; T2K; NF-kB-activating kinase; NF-kappa-B-activating kinase; Serine/threonine-protein kinase TBK1
Chromosomal Location	12q14.2
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 TBK1 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	-0.085	0.74
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	0.163	0.922
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	-0.262	0.823
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	-0.077	0.84
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	-0.185	0.916
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0.056	0.979
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	0.081	0.816
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	0.122	0.939
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	0.073	0.966
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	0.386	0.72
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	0.594	0.727
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	0.114	0.0907

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of TBK1 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	0	0	0	1
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	0	0	0	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	3.7	0	3.7	0.27
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	0	0	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	3.7	0	3.7	0.314
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	0	5.9	-5.9	0.447
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	0	16.7	-16.7	0.429
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	0	6.2	-6.2	1
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0	11.1	-11.1	1
12	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0	0	0	1
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	5.3	0	5.3	0.507
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	4.5	0	4.5	1
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	6.2	0	6.2	1
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	TBK1
Name	TANK-binding kinase 1
Aliases	NAK; T2K; NF-kB-activating kinase; NF-kappa-B-activating kinase; Serine/threonine-protein kinase TBK1
Chromosomal Location	12q14.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of TBK1. 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	TBK1
Name	TANK-binding kinase 1
Aliases	NAK; T2K; NF-kB-activating kinase; NF-kappa-B-activating kinase; Serine/threonine-protein kinase TBK1
Chromosomal Location	12q14.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of TBK1. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by TBK1. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	TBK1
Name	TANK-binding kinase 1
Aliases	NAK; T2K; NF-kB-activating kinase; NF-kappa-B-activating kinase; Serine/threonine-protein kinase TBK1
Chromosomal Location	12q14.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of TBK1. 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	TBK1
Name	TANK-binding kinase 1
Aliases	NAK; T2K; NF-kB-activating kinase; NF-kappa-B-activating kinase; Serine/threonine-protein kinase TBK1
Chromosomal Location	12q14.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of TBK1 expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	TBK1
Name	TANK-binding kinase 1
Aliases	NAK; T2K; NF-kB-activating kinase; NF-kappa-B-activating kinase; Serine/threonine-protein kinase TBK1
Chromosomal Location	12q14.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between TBK1 and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	TBK1
Name	TANK-binding kinase 1
Aliases	NAK; T2K; NF-kB-activating kinase; NF-kappa-B-activating kinase; Serine/threonine-protein kinase TBK1
Chromosomal Location	12q14.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting TBK1 collected from DrugBank database.

> Drugs from DrugBank database [ TOP ]
There is no record.

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