TISIDB

Summary
Symbol	MAP3K9
Name	mitogen-activated protein kinase kinase kinase 9
Aliases	PRKE1; MEKK9; MLK1; mixed lineage kinase 1 (tyr and ser/thr specificity); Mixed lineage kinase 1
Chromosomal Location	14q24.2
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	-
Domain	PF00069 Protein kinase domain PF14604 Variant SH3 domain
Function	Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade through the phosphorylation of MAP2K4/MKK4 and MAP2K7/MKK7 which in turn activate the JNKs. The MKK/JNK signaling pathway regulates stress response via activator protein-1 (JUN) and GATA4 transcription factors. Plays also a role in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis.

> Gene Ontology [ TOP ]
Biological Process	GO:0000186 activation of MAPKK activity GO:0000187 activation of MAPK activity GO:0007254 JNK cascade GO:0007256 activation of JNKK activity GO:0007257 activation of JUN kinase activity GO:0031098 stress-activated protein kinase signaling cascade GO:0032147 activation of protein kinase activity GO:0032872 regulation of stress-activated MAPK cascade GO:0032874 positive regulation of stress-activated MAPK cascade GO:0033674 positive regulation of kinase activity GO:0043405 regulation of MAP kinase activity GO:0043406 positive regulation of MAP kinase activity GO:0043410 positive regulation of MAPK cascade GO:0043506 regulation of JUN kinase activity GO:0043507 positive regulation of JUN kinase activity GO:0045860 positive regulation of protein kinase activity GO:0046328 regulation of JNK cascade GO:0046330 positive regulation of JNK cascade GO:0046777 protein autophosphorylation GO:0051403 stress-activated MAPK cascade GO:0070302 regulation of stress-activated protein kinase signaling cascade GO:0070304 positive regulation of stress-activated protein kinase signaling cascade GO:0071900 regulation of protein serine/threonine kinase activity GO:0071902 positive regulation of protein serine/threonine kinase activity
Molecular Function	GO:0004674 protein serine/threonine kinase activity GO:0004702 receptor signaling protein serine/threonine kinase activity GO:0004706 JUN kinase kinase kinase activity GO:0004708 MAP kinase kinase activity GO:0004709 MAP kinase kinase kinase activity GO:0004712 protein serine/threonine/tyrosine kinase activity GO:0005057 receptor signaling protein activity
Cellular Component	-

> KEGG and Reactome Pathway [ TOP ]
KEGG	-
Reactome	-

Summary
Symbol	MAP3K9
Name	mitogen-activated protein kinase kinase kinase 9
Aliases	PRKE1; MEKK9; MLK1; mixed lineage kinase 1 (tyr and ser/thr specificity); Mixed lineage kinase 1
Chromosomal Location	14q24.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between MAP3K9 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 [ TOP ]
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Summary
Symbol	MAP3K9
Name	mitogen-activated protein kinase kinase kinase 9
Aliases	PRKE1; MEKK9; MLK1; mixed lineage kinase 1 (tyr and ser/thr specificity); Mixed lineage kinase 1
Chromosomal Location	14q24.2
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 MAP3K9 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	MAP3K9
Name	mitogen-activated protein kinase kinase kinase 9
Aliases	PRKE1; MEKK9; MLK1; mixed lineage kinase 1 (tyr and ser/thr specificity); Mixed lineage kinase 1
Chromosomal Location	14q24.2
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 MAP3K9 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	0.644	0.0342
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	0.845	0.106
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	0.492	0.286
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0.245	0.588
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0.278	0.88
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0.21	0.933
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	0.602	0.253
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	1.025	0.195
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	0.135	0.873
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	-0.248	0.533
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	-0.077	0.892
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	0.099	0.423

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of MAP3K9 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	14.8	4.1	10.7	0.0828
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	14.8	5.1	9.7	0.199
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	14.3	0	14.3	0.238
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	25	0	25	0.473
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	7.7	0	7.7	1
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0	0	0	1
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	0	0	0	1
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	10.5	3.7	6.8	0.393
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	13.6	7.7	5.9	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	MAP3K9
Name	mitogen-activated protein kinase kinase kinase 9
Aliases	PRKE1; MEKK9; MLK1; mixed lineage kinase 1 (tyr and ser/thr specificity); Mixed lineage kinase 1
Chromosomal Location	14q24.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of MAP3K9. 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	MAP3K9
Name	mitogen-activated protein kinase kinase kinase 9
Aliases	PRKE1; MEKK9; MLK1; mixed lineage kinase 1 (tyr and ser/thr specificity); Mixed lineage kinase 1
Chromosomal Location	14q24.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of MAP3K9. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by MAP3K9. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	MAP3K9
Name	mitogen-activated protein kinase kinase kinase 9
Aliases	PRKE1; MEKK9; MLK1; mixed lineage kinase 1 (tyr and ser/thr specificity); Mixed lineage kinase 1
Chromosomal Location	14q24.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of MAP3K9. 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	MAP3K9
Name	mitogen-activated protein kinase kinase kinase 9
Aliases	PRKE1; MEKK9; MLK1; mixed lineage kinase 1 (tyr and ser/thr specificity); Mixed lineage kinase 1
Chromosomal Location	14q24.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of MAP3K9 expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	MAP3K9
Name	mitogen-activated protein kinase kinase kinase 9
Aliases	PRKE1; MEKK9; MLK1; mixed lineage kinase 1 (tyr and ser/thr specificity); Mixed lineage kinase 1
Chromosomal Location	14q24.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between MAP3K9 and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	MAP3K9
Name	mitogen-activated protein kinase kinase kinase 9
Aliases	PRKE1; MEKK9; MLK1; mixed lineage kinase 1 (tyr and ser/thr specificity); Mixed lineage kinase 1
Chromosomal Location	14q24.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting MAP3K9 collected from DrugBank database.

> Drugs from DrugBank database

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Details on drugs targeting MAP3K9.

ID	Name	Drug Type	Targets	#Targets
DB08703	12-(2-hydroxyethyl)-2-(1-methylethoxy)-13,14-dihydronaphtho[2,1-a]pyrrolo[3,4-c]carbazol-5(12H)-one	Small Molecule	MAP3K9	1

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