MAP4K4 Gene

HGNC Family	Mitogen-activated protein kinase cascade
Name	mitogen-activated protein kinase kinase kinase kinase 4
Description	The protein encoded by this gene is a member of the serine/threonine protein kinase family. This kinase has been shown to specifically activate MAPK8/JNK. The activation of MAPK8 by this kinase is found to be inhibited by the dominant-negative mutants of MAP3K7/TAK1, MAP2K4/MKK4, and MAP2K7/MKK7, which suggests that this kinase may function through the MAP3K7-MAP2K4-MAP2K7 kinase cascade, and mediate the TNF-alpha signaling pathway. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n MAP4K4 is a serine/threonine kinase that has emerged as a multifunctional regulator linking inflammatory cues, metabolic homeostasis, and oncogenic cell behavior. In metabolic tissues such as adipose and skeletal muscle, elevated MAP4K4 expression—stimulated by pro‐inflammatory factors (for example, TNF‑α via TNFR1 signaling)—inhibits key adipogenic transcription factors (including PPARγ) and down‑regulates GLUT4 expression. This interference disrupts normal adipocyte differentiation and impairs insulin‐mediated glucose uptake, thereby contributing to insulin resistance (see."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In parallel, MAP4K4 modulates intracellular stress and inflammatory signaling by activating downstream kinases such as JNK and engaging the NF‑κB pathway. Enhanced stability or up‑regulation of MAP4K4 mRNA can promote the production of proinflammatory cytokines, further exacerbating inflammatory responses (see"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the context of cancer, MAP4K4 is associated with increased cell migration, invasion, and tumor progression. Its activity promotes cytoskeletal remodeling and focal adhesion turnover—for example, through interactions that trigger Arf6 activation—thereby facilitating cell motility. Moreover, oncogenic signals such as those emanating from mutant EGFRvIII induce MAP4K4 expression to establish autocrine growth loops, while its overexpression is correlated with poor clinical outcomes in malignancies including pancreatic and hepatocellular carcinomas (see."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Furthermore, tumor‐suppressive microRNAs—including miR‑141 and miR‑194—have been shown to directly target MAP4K4, thereby attenuating cancer cell proliferation, invasion, and chemoresistance. This microRNA‐mediated regulation places MAP4K4 at a critical nexus in controlling oncogenic signaling networks (see"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings highlight MAP4K4 as an important integrator of pro‑inflammatory, metabolic, and cytoskeletal signals. Its regulation of insulin signaling in metabolic tissues and promotion of cell motility and invasion in cancer cells underscore its potential as a therapeutic target in both metabolic disorders and malignancies.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Petter Isakson, Ann Hammarstedt, Birgit Gustafson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Impaired preadipocyte differentiation in human abdominal obesity: role of Wnt, tumor necrosis factor-alpha, and inflammation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Diabetes (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2337/db08-1770"}], "href": "https://doi.org/10.2337/db08-1770"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19351711"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19351711"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Xiaoqing Tang, Adilson Guilherme, Abhijit Chakladar, et al. "}, {"type": "b", "children": [{"type": "t", "text": "An RNA interference-based screen identifies MAP4K4/NIK as a negative regulator of PPARgamma, adipogenesis, and insulin-responsive hexose transport."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0507660103"}], "href": "https://doi.org/10.1073/pnas.0507660103"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16461467"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16461467"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Gregory J Tesz, Adilson Guilherme, Kalyani V P Guntur, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tumor necrosis factor alpha (TNFalpha) stimulates Map4k4 expression through TNFalpha receptor 1 signaling to c-Jun and activating transcription factor 2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M700665200"}], "href": "https://doi.org/10.1074/jbc.M700665200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17500068"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17500068"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Karim Bouzakri, Juleen R Zierath "}, {"type": "b", "children": [{"type": "t", "text": "MAP4K4 gene silencing in human skeletal muscle prevents tumor necrosis factor-alpha-induced insulin resistance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M608602200"}], "href": "https://doi.org/10.1074/jbc.M608602200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17227768"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17227768"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Ruiqing Yu, Qimeng Li, Zhihui Feng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "m6A Reader YTHDF2 Regulates LPS-Induced Inflammatory Response."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms20061323"}], "href": "https://doi.org/10.3390/ijms20061323"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30875984"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30875984"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Noriko Machida, Masato Umikawa, Kimiko Takei, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mitogen-activated protein kinase kinase kinase kinase 4 as a putative effector of Rap2 to activate the c-Jun N-terminal kinase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.C300542200"}], "href": "https://doi.org/10.1074/jbc.C300542200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14966141"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14966141"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Cynthia S Collins, Jiyong Hong, Lisa Sapinoso, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A small interfering RNA screen for modulators of tumor cell motility identifies MAP4K4 as a promigratory kinase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0600040103"}], "href": "https://doi.org/10.1073/pnas.0600040103"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16537454"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16537454"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Jiping Yue, Min Xie, Xuewen Gou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Microtubules regulate focal adhesion dynamics through MAP4K4."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Cell (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.devcel.2014.10.025"}], "href": "https://doi.org/10.1016/j.devcel.2014.10.025"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25490267"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25490267"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Deepti B Ramnarain, Seongmi Park, Diana Y Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Differential gene expression analysis reveals generation of an autocrine loop by a mutant epidermal growth factor receptor in glioma cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-05-2753"}], "href": "https://doi.org/10.1158/0008-5472.CAN-05-2753"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16424019"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16424019"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "John J Liang, Hua Wang, Asif Rashid, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression of MAP4K4 is associated with worse prognosis in patients with stage II pancreatic ductal adenocarcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-08-0381"}], "href": "https://doi.org/10.1158/1078-0432.CCR-08-0381"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18981001"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18981001"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "An-Wen Liu, Jing Cai, Xiang-Li Zhao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ShRNA-targeted MAP4K4 inhibits hepatocellular carcinoma growth."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-10-0331"}], "href": "https://doi.org/10.1158/1078-0432.CCR-10-0331"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21196414"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21196414"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Gang Zhao, Bo Wang, Yang Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miRNA-141, downregulated in pancreatic cancer, inhibits cell proliferation and invasion by directly targeting MAP4K4."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cancer Ther (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1535-7163.MCT-13-0296"}], "href": "https://doi.org/10.1158/1535-7163.MCT-13-0296"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24013097"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24013097"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Xuchao Zhu, Dan Li, Fei Yu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miR-194 inhibits the proliferation, invasion, migration, and enhances the chemosensitivity of non-small cell lung cancer cells by targeting forkhead box A1 protein."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.7545"}], "href": "https://doi.org/10.18632/oncotarget.7545"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26909612"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26909612"}]}]}]}
Synonyms	HEL-S-31, FLH21957, MEKKK4, HGK
Proteins	M4K4_HUMAN
NCBI Gene ID	9448
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

MAP4K4 has 15,649 functional associations with biological entities spanning 9 categories (molecular profile, organism, functional term, phrase or reference, chemical, disease, phenotype or trait, structural feature, cell line, cell type or tissue, gene, protein or microRNA, sequence feature) extracted from 135 datasets.

Click the + buttons to view associations for MAP4K4 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

MAP4K4 Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of MAP4K4 gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of MAP4K4 gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of MAP4K4 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of MAP4K4 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of MAP4K4 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of MAP4K4 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	Biocarta Pathways	pathways involving MAP4K4 protein from the Biocarta Pathways dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of MAP4K4 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of MAP4K4 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of MAP4K4 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	Carcinogenome Chemical Perturbation Carcinogenicity Signatures	small molecule perturbations changing expression of MAP4K4 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of MAP4K4 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of MAP4K4 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Gene Mutation Profiles	cell lines with MAP4K4 gene mutations from the CCLE Cell Line Gene Mutation Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with MAP4K4 protein from the CCLE Cell Line Proteomics dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with MAP4K4 gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of MAP4K4 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of MAP4K4 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of MAP4K4 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of MAP4K4 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing MAP4K4 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing MAP4K4 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with MAP4K4 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with MAP4K4 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	CORUM Protein Complexes	protein complexs containing MAP4K4 protein from the CORUM Protein Complexes dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of MAP4K4 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with MAP4K4 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with MAP4K4 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with MAP4K4 gene/protein from the curated CTD Gene-Disease Associations dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of MAP4K4 protein relative to other small molecule perturbations from the DeepCoverMOA Drug Mechanisms of Action dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by MAP4K4 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with MAP4K4 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with MAP4K4 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with MAP4K4 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with MAP4K4 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at MAP4K4 gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of MAP4K4 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of MAP4K4 gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing MAP4K4 from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GDSC Cell Line Gene Expression Profiles	cell lines with high or low expression of MAP4K4 gene relative to other cell lines from the GDSC Cell Line Gene Expression Profiles dataset.