TISIDB

Summary
Symbol	MAP2K7
Name	mitogen-activated protein kinase kinase 7
Aliases	MKK7; Jnkk2; PRKMK7; MAPKK7; MEK; MEK 7; SAPKK-4; SAPKK4; JNK-activating kinase 2; MAP kinase kinase 7; MAPK ......
Chromosomal Location	19p13.3-p13.2
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	Nucleus. Cytoplasm
Domain	PF00069 Protein kinase domain
Function	Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Essential component of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. With MAP2K4/MKK4, is the one of the only known kinase to directly activate the stress-activated protein kinase/c-Jun N-terminal kinases MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. MAP2K4/MKK4 and MAP2K7/MKK7 both activate the JNKs by phosphorylation, but they differ in their preference for the phosphorylation site in the Thr-Pro-Tyr motif. MAP2K4/MKK4 shows preference for phosphorylation of the Tyr residue and MAP2K7/MKK7 for the Thr residue. The monophosphorylation of JNKs on the Thr residue is sufficient to increase JNK activity indicating that MAP2K7/MKK7 is important to trigger JNK activity, while the additional phosphorylation of the Tyr residue by MAP2K4/MKK4 ensures optimal JNK activation. Has a specific role in JNK signal transduction pathway activated by proinflammatory cytokines. The MKK/JNK signaling pathway is also involved in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis.

> Gene Ontology [ TOP ]
Biological Process	GO:0000187 activation of MAPK activity GO:0000723 telomere maintenance GO:0002764 immune response-regulating signaling pathway GO:0002768 immune response-regulating cell surface receptor signaling pathway GO:0006278 RNA-dependent DNA biosynthetic process GO:0006970 response to osmotic stress GO:0007004 telomere maintenance via telomerase GO:0007254 JNK cascade GO:0007257 activation of JUN kinase activity GO:0009266 response to temperature stimulus GO:0009314 response to radiation GO:0009408 response to heat GO:0009411 response to UV GO:0009416 response to light stimulus GO:0010833 telomere maintenance via telomere lengthening GO:0016233 telomere capping GO:0018108 peptidyl-tyrosine phosphorylation GO:0018212 peptidyl-tyrosine modification GO:0031098 stress-activated protein kinase signaling cascade GO:0032147 activation of protein kinase activity GO:0032200 telomere organization GO:0032204 regulation of telomere maintenance GO:0032206 positive regulation of telomere maintenance GO:0032210 regulation of telomere maintenance via telomerase GO:0032212 positive regulation of telomere maintenance via telomerase GO:0032844 regulation of homeostatic process GO:0032846 positive regulation of homeostatic process GO:0032872 regulation of stress-activated MAPK cascade GO:0032874 positive regulation of stress-activated MAPK cascade GO:0033044 regulation of chromosome organization GO:0033674 positive regulation of kinase activity GO:0034612 response to tumor necrosis factor GO:0035897 proteolysis in other organism GO:0038093 Fc receptor signaling pathway GO:0038095 Fc-epsilon receptor signaling pathway 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:0044033 multi-organism metabolic process GO:0045860 positive regulation of protein kinase activity GO:0046328 regulation of JNK cascade GO:0046330 positive regulation of JNK cascade GO:0051052 regulation of DNA metabolic process GO:0051054 positive regulation of DNA metabolic process GO:0051403 stress-activated MAPK cascade GO:0051972 regulation of telomerase activity GO:0051973 positive regulation of telomerase activity GO:0060249 anatomical structure homeostasis GO:0070302 regulation of stress-activated protein kinase signaling cascade GO:0070304 positive regulation of stress-activated protein kinase signaling cascade GO:0071897 DNA biosynthetic process GO:0071900 regulation of protein serine/threonine kinase activity GO:0071902 positive regulation of protein serine/threonine kinase activity GO:1904353 regulation of telomere capping GO:1904355 positive regulation of telomere capping GO:1904356 regulation of telomere maintenance via telomere lengthening GO:1904358 positive regulation of telomere maintenance via telomere lengthening GO:2000278 regulation of DNA biosynthetic process GO:2000573 positive regulation of DNA biosynthetic process GO:2001252 positive regulation of chromosome organization
Molecular Function	GO:0000287 magnesium ion binding GO:0004674 protein serine/threonine kinase activity GO:0004702 receptor signaling protein serine/threonine kinase activity GO:0004708 MAP kinase kinase activity GO:0004712 protein serine/threonine/tyrosine kinase activity GO:0004713 protein tyrosine kinase activity GO:0005057 receptor signaling protein activity GO:0019902 phosphatase binding GO:0019903 protein phosphatase binding
Cellular Component	-

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa04010 MAPK signaling pathway hsa04012 ErbB signaling pathway hsa04141 Protein processing in endoplasmic reticulum hsa04380 Osteoclast differentiation hsa04530 Tight junction hsa04620 Toll-like receptor signaling pathway hsa04660 T cell receptor signaling pathway hsa04664 Fc epsilon RI signaling pathway hsa04668 TNF signaling pathway hsa04722 Neurotrophin signaling pathway hsa04912 GnRH signaling pathway
Reactome	R-HSA-166054: Activated TLR4 signalling R-HSA-2559583: Cellular Senescence R-HSA-2262752: Cellular responses to stress R-HSA-1643685: Disease R-HSA-2871796: FCERI mediated MAPK activation R-HSA-2454202: Fc epsilon receptor (FCERI) signaling R-HSA-168256: Immune System R-HSA-5663205: Infectious disease R-HSA-168249: Innate Immune System R-HSA-450321: JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 R-HSA-450294: MAP kinase activation in TLR cascade R-HSA-975871: MyD88 cascade initiated on plasma membrane R-HSA-975155: MyD88 dependent cascade initiated on endosome R-HSA-166166: MyD88-independent TLR3/TLR4 cascade R-HSA-166058: MyD88 R-HSA-2559580: Oxidative Stress Induced Senescence R-HSA-168180: TRAF6 Mediated Induction of proinflammatory cytokines R-HSA-975138: TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation R-HSA-937061: TRIF-mediated TLR3/TLR4 signaling R-HSA-168142: Toll Like Receptor 10 (TLR10) Cascade R-HSA-181438: Toll Like Receptor 2 (TLR2) Cascade R-HSA-168164: Toll Like Receptor 3 (TLR3) Cascade R-HSA-166016: Toll Like Receptor 4 (TLR4) Cascade R-HSA-168176: Toll Like Receptor 5 (TLR5) Cascade R-HSA-168181: Toll Like Receptor 7/8 (TLR7/8) Cascade R-HSA-168138: Toll Like Receptor 9 (TLR9) Cascade R-HSA-168179: Toll Like Receptor TLR1 R-HSA-168188: Toll Like Receptor TLR6 R-HSA-168898: Toll-Like Receptors Cascades R-HSA-5339562: Uptake and actions of bacterial toxins R-HSA-5210891: Uptake and function of anthrax toxins

> KEGG and Reactome Pathway

[ TOP ]

KEGG

hsa04010 MAPK signaling pathway
hsa04012 ErbB signaling pathway
hsa04141 Protein processing in endoplasmic reticulum
hsa04380 Osteoclast differentiation
hsa04530 Tight junction
hsa04620 Toll-like receptor signaling pathway
hsa04660 T cell receptor signaling pathway
hsa04664 Fc epsilon RI signaling pathway
hsa04668 TNF signaling pathway
hsa04722 Neurotrophin signaling pathway
hsa04912 GnRH signaling pathway

Reactome

R-HSA-166054: Activated TLR4 signalling
R-HSA-2559583: Cellular Senescence
R-HSA-2262752: Cellular responses to stress
R-HSA-1643685: Disease
R-HSA-2871796: FCERI mediated MAPK activation
R-HSA-2454202: Fc epsilon receptor (FCERI) signaling
R-HSA-168256: Immune System
R-HSA-5663205: Infectious disease
R-HSA-168249: Innate Immune System
R-HSA-450321: JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1
R-HSA-450294: MAP kinase activation in TLR cascade
R-HSA-975871: MyD88 cascade initiated on plasma membrane
R-HSA-975155: MyD88 dependent cascade initiated on endosome
R-HSA-166166: MyD88-independent TLR3/TLR4 cascade
R-HSA-166058: MyD88
R-HSA-2559580: Oxidative Stress Induced Senescence
R-HSA-168180: TRAF6 Mediated Induction of proinflammatory cytokines
R-HSA-975138: TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation
R-HSA-937061: TRIF-mediated TLR3/TLR4 signaling
R-HSA-168142: Toll Like Receptor 10 (TLR10) Cascade
R-HSA-181438: Toll Like Receptor 2 (TLR2) Cascade
R-HSA-168164: Toll Like Receptor 3 (TLR3) Cascade
R-HSA-166016: Toll Like Receptor 4 (TLR4) Cascade
R-HSA-168176: Toll Like Receptor 5 (TLR5) Cascade
R-HSA-168181: Toll Like Receptor 7/8 (TLR7/8) Cascade
R-HSA-168138: Toll Like Receptor 9 (TLR9) Cascade
R-HSA-168179: Toll Like Receptor TLR1
R-HSA-168188: Toll Like Receptor TLR6
R-HSA-168898: Toll-Like Receptors Cascades
R-HSA-5339562: Uptake and actions of bacterial toxins
R-HSA-5210891: Uptake and function of anthrax toxins

Summary
Symbol	MAP2K7
Name	mitogen-activated protein kinase kinase 7
Aliases	MKK7; Jnkk2; PRKMK7; MAPKK7; MEK; MEK 7; SAPKK-4; SAPKK4; JNK-activating kinase 2; MAP kinase kinase 7; MAPK ......
Chromosomal Location	19p13.3-p13.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between MAP2K7 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 MAP2K7 and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
26515496	Breast Carcinoma	Biomarker of response to immunotherapy	Furthermore, Ras/MAPK activation and MHC expression may be predictive biomarkers of response to immune checkpoint inhibitors.
26944201	Colon Carcinoma	Inhibit immunity (T cell function), resistant to immunotherapy	Thus, despite the central importance of the MAP kinase pathway in some aspects of T cell function, MEK-targeted agents can be compatible with T-cell-dependent immunotherapy.
25787767	Melanoma	Inhibit immunity (T cell function)	Our findings support the testing of triple combination therapy of BRAF and MEK inhibitors with immunotherapy in patients with BRAF(V600E) mutant metastatic melanoma.
29650805	melanoma	Inhibit immunity	Transcriptomic and proteomic analysis revealed that combining BET and MEK inhibitors mitigates a MAPK and checkpoint inhibitor resistance transcriptional signature, downregulates the transcription factor TCF19, and induces apoptosis.
29843107	Melanoma	Resistant to immunotherapy	MEK inhibition may increase survival of NRAS-mutated melanoma patients treated with checkpoint blockade: Results of a retrospective multicentre analysis of 364 patients. Therapy with oral MEK inhibitors before or after checkpoint inhibitor therapy showed a trend toward a survival benefit in patients with NRAS mutant melanoma.
16801397	Melanoma	Inhibit immunity	Here, we demonstrate a novel role of the activated MAPK pathway in immune evasion by melanoma cells with the mutation of BRAF, which encodes a MAPKKs, (BRAF(V600E)). MEK inhibitor U0126 or RNA interference (RNAi) for BRAF(V600E) decreased production of the immunosuppressive soluble factors interleukin (IL)-10, VEGF, or IL-6 from melanoma cells to levels comparable to those after signal transducer and activator of transcription (STAT)3 inactivation

Summary
Symbol	MAP2K7
Name	mitogen-activated protein kinase kinase 7
Aliases	MKK7; Jnkk2; PRKMK7; MAPKK7; MEK; MEK 7; SAPKK-4; SAPKK4; JNK-activating kinase 2; MAP kinase kinase 7; MAPK ......
Chromosomal Location	19p13.3-p13.2
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 MAP2K7 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	MAP2K7
Name	mitogen-activated protein kinase kinase 7
Aliases	MKK7; Jnkk2; PRKMK7; MAPKK7; MEK; MEK 7; SAPKK-4; SAPKK4; JNK-activating kinase 2; MAP kinase kinase 7; MAPK ......
Chromosomal Location	19p13.3-p13.2
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 MAP2K7 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	-0.181	0.385
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	-0.336	0.858
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	-0.071	0.96
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0.005	0.984
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0.113	0.949
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	-0.132	0.954
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	0.111	0.714
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	0.064	0.961
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	0.14	0.926
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	0.295	0.817
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	0.427	0.815
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	-0.042	0.501

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of MAP2K7 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	Pval
1	25765070	Non-small cell lung cancer (NSCLC)	all	Anti-PD-1 (pembrolizumab)	14	17	1
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	1
3	25765070	Non-small cell lung cancer (NSCLC)	non-smoking	Anti-PD-1 (pembrolizumab)	4	14	1
4	26359337	Melanoma	all	Anti-CTLA-4 (ipilimumab)	27	73	1
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	1
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	1
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	1
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	1
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	1
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	1
12	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	1
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	1
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	1
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	1
16	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	11	13	1
17	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	6	1	1
18	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	5	12	1

Summary
Symbol	MAP2K7
Name	mitogen-activated protein kinase kinase 7
Aliases	MKK7; Jnkk2; PRKMK7; MAPKK7; MEK; MEK 7; SAPKK-4; SAPKK4; JNK-activating kinase 2; MAP kinase kinase 7; MAPK ......
Chromosomal Location	19p13.3-p13.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of MAP2K7. 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	MAP2K7
Name	mitogen-activated protein kinase kinase 7
Aliases	MKK7; Jnkk2; PRKMK7; MAPKK7; MEK; MEK 7; SAPKK-4; SAPKK4; JNK-activating kinase 2; MAP kinase kinase 7; MAPK ......
Chromosomal Location	19p13.3-p13.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of MAP2K7. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by MAP2K7. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	MAP2K7
Name	mitogen-activated protein kinase kinase 7
Aliases	MKK7; Jnkk2; PRKMK7; MAPKK7; MEK; MEK 7; SAPKK-4; SAPKK4; JNK-activating kinase 2; MAP kinase kinase 7; MAPK ......
Chromosomal Location	19p13.3-p13.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of MAP2K7. 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	MAP2K7
Name	mitogen-activated protein kinase kinase 7
Aliases	MKK7; Jnkk2; PRKMK7; MAPKK7; MEK; MEK 7; SAPKK-4; SAPKK4; JNK-activating kinase 2; MAP kinase kinase 7; MAPK ......
Chromosomal Location	19p13.3-p13.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of MAP2K7 expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	MAP2K7
Name	mitogen-activated protein kinase kinase 7
Aliases	MKK7; Jnkk2; PRKMK7; MAPKK7; MEK; MEK 7; SAPKK-4; SAPKK4; JNK-activating kinase 2; MAP kinase kinase 7; MAPK ......
Chromosomal Location	19p13.3-p13.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between MAP2K7 and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	MAP2K7
Name	mitogen-activated protein kinase kinase 7
Aliases	MKK7; Jnkk2; PRKMK7; MAPKK7; MEK; MEK 7; SAPKK-4; SAPKK4; JNK-activating kinase 2; MAP kinase kinase 7; MAPK ......
Chromosomal Location	19p13.3-p13.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting MAP2K7 collected from DrugBank database.

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

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