MAP4K4

MAP4K4
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4OBO, 4OBP, 4OBQ, 4RVT, 4U43, 4U44, 4U45, 4ZK5, 4U42, 5DI1, 4U3Y, 4U3Z, 4U41, 4U40
Identifiers
Aliases	MAP4K4, FLH21957, HEL-S-31, HGK, MEKKK4, NIK, mitogen-activated protein kinase kinase kinase kinase 4
External IDs	MGI: 1349394 HomoloGene: 7442 GeneCards: MAP4K4
Gene ontology Molecular function • transferase activity • creatine kinase activity • protein serine/threonine kinase activity • nucleotide binding • protein kinase activity • protein binding • ATP binding • kinase activity • signal transducer, downstream of receptor, with serine/threonine kinase activity Cellular component • cytoplasm Biological process • protein phosphorylation • regulation of JNK cascade • intracellular signal transduction • negative regulation of apoptotic process • microvillus assembly • phosphorylation • signal transduction by protein phosphorylation Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	9448	26921
Ensembl	ENSG00000071054	ENSMUSG00000026074
UniProt	O95819	P97820
RefSeq (mRNA)	NM_001242559 NM_001242560 NM_004834 NM_145686 NM_145687	NM_001252200 NM_001252201 NM_001252202 NM_008696
RefSeq (protein)	NP_001229488.1 NP_004825.3 NP_663720.1	NP_001239129.1 NP_001239130.1 NP_001239131.1 NP_032722.2
Location (UCSC)	Chr 2: 101.7 – 101.89 Mb	Chr 1: 39.9 – 40.03 Mb
PubMed search	[1]	[2]
Wikidata

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Mitogen-activated protein kinase kinase kinase kinase 4 is an enzyme that in humans is encoded by the MAP4K4 gene.^[3][4][5][6]

Function

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.^[6] A recent study showed that MAP4K4 is a direct kinase of LATS1/2 and thus regulates the Hippo pathway effectors YAP and TAZ. ^[7][8]

Interactions

MAP4K4 has been shown to interact with NCK1^[5] and CD29.^[9]

References

1. "Human PubMed Reference:".
2. "Mouse PubMed Reference:".
3. Yao Z, Zhou G, Wang XS, Brown A, Diener K, Gan H, Tan TH (Jan 1999). "A novel human STE20-related protein kinase, HGK, that specifically activates the c-Jun N-terminal kinase signaling pathway". The Journal of Biological Chemistry. 274 (4): 2118–25. doi:10.1074/jbc.274.4.2118. PMID 9890973.
4. Ishikawa K, Nagase T, Suyama M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O (Jun 1998). "Prediction of the coding sequences of unidentified human genes. X. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro". DNA Research. 5 (3): 169–76. doi:10.1093/dnares/5.3.169. PMID 9734811.
5. Su YC, Han J, Xu S, Cobb M, Skolnik EY (Mar 1997). "NIK is a new Ste20-related kinase that binds NCK and MEKK1 and activates the SAPK/JNK cascade via a conserved regulatory domain". The EMBO Journal. 16 (6): 1279–90. doi:10.1093/emboj/16.6.1279. PMC 1169726. PMID 9135144.
6. "Entrez Gene: MAP4K4 mitogen-activated protein kinase kinase kinase kinase 4".
7. Meng, Zhipeng; Moroishi, Toshiro; Mottier-Pavie, Violaine; Plouffe, Steven W.; Hansen, Carsten G.; Hong, Audrey W.; Park, Hyun Woo; Mo, Jung-Soon; Lu, Wenqi (2015-10-05). "MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway". Nature Communications. 6: 8357. doi:10.1038/ncomms9357. PMC 4600732. PMID 26437443.
8. Meng, Zhipeng; Moroishi, Toshiro; Guan, Kun-Liang (2016-01-01). "Mechanisms of Hippo pathway regulation". Genes & Development. 30 (1): 1–17. doi:10.1101/gad.274027.115. ISSN 0890-9369. PMC 4701972. PMID 26728553.
9. Poinat P, De Arcangelis A, Sookhareea S, Zhu X, Hedgecock EM, Labouesse M, Georges-Labouesse E (Apr 2002). "A conserved interaction between beta1 integrin/PAT-3 and Nck-interacting kinase/MIG-15 that mediates commissural axon navigation in C. elegans". Current Biology. 12 (8): 622–31. doi:10.1016/S0960-9822(02)00764-9. PMID 11967148.

Further reading

• Becker E, Huynh-Do U, Holland S, Pawson T, Daniel TO, Skolnik EY (Mar 2000). "Nck-interacting Ste20 kinase couples Eph receptors to c-Jun N-terminal kinase and integrin activation". Molecular and Cellular Biology. 20 (5): 1537–45. doi:10.1128/MCB.20.5.1537-1545.2000. PMC 85333. PMID 10669731.
• Zhao ZS, Manser E, Lim L (Jun 2000). "Interaction between PAK and nck: a template for Nck targets and role of PAK autophosphorylation". Molecular and Cellular Biology. 20 (11): 3906–17. doi:10.1128/MCB.20.11.3906-3917.2000. PMC 85736. PMID 10805734.
• Hofer-Warbinek R, Schmid JA, Stehlik C, Binder BR, Lipp J, de Martin R (Jul 2000). "Activation of NF-kappa B by XIAP, the X chromosome-linked inhibitor of apoptosis, in endothelial cells involves TAK1". The Journal of Biological Chemistry. 275 (29): 22064–8. doi:10.1074/jbc.M910346199. PMID 10807933.
• Chaudhary PM, Eby MT, Jasmin A, Kumar A, Liu L, Hood L (Sep 2000). "Activation of the NF-kappaB pathway by caspase 8 and its homologs". Oncogene. 19 (39): 4451–60. doi:10.1038/sj.onc.1203812. PMID 11002417.
• Yan W, Nehrke K, Choi J, Barber DL (Aug 2001). "The Nck-interacting kinase (NIK) phosphorylates the Na+-H+ exchanger NHE1 and regulates NHE1 activation by platelet-derived growth factor". The Journal of Biological Chemistry. 276 (33): 31349–56. doi:10.1074/jbc.M102679200. PMID 11369779.
• Poinat P, De Arcangelis A, Sookhareea S, Zhu X, Hedgecock EM, Labouesse M, Georges-Labouesse E (Apr 2002). "A conserved interaction between beta1 integrin/PAT-3 and Nck-interacting kinase/MIG-15 that mediates commissural axon navigation in C. elegans". Current Biology. 12 (8): 622–31. doi:10.1016/S0960-9822(02)00764-9. PMID 11967148.
• Fong A, Zhang M, Neely J, Sun SC (Oct 2002). "S9, a 19 S proteasome subunit interacting with ubiquitinated NF-kappaB2/p100". The Journal of Biological Chemistry. 277 (43): 40697–702. doi:10.1074/jbc.M205330200. PMID 12185077.
• Luan Z, Zhang Y, Liu A, Man Y, Cheng L, Hu G (Oct 2002). "A novel GTP-binding protein hGBP3 interacts with NIK/HGK". FEBS Letters. 530 (1-3): 233–8. doi:10.1016/S0014-5793(02)03467-1. PMID 12387898.
• Wright JH, Wang X, Manning G, LaMere BJ, Le P, Zhu S, Khatry D, Flanagan PM, Buckley SD, Whyte DB, Howlett AR, Bischoff JR, Lipson KE, Jallal B (Mar 2003). "The STE20 kinase HGK is broadly expressed in human tumor cells and can modulate cellular transformation, invasion, and adhesion". Molecular and Cellular Biology. 23 (6): 2068–82. doi:10.1128/MCB.23.6.2068-2082.2003. PMC 149462. PMID 12612079.
• Rodriguez M, Yu X, Chen J, Songyang Z (Dec 2003). "Phosphopeptide binding specificities of BRCA1 COOH-terminal (BRCT) domains". The Journal of Biological Chemistry. 278 (52): 52914–8. doi:10.1074/jbc.C300407200. PMID 14578343.
• Machida N, Umikawa M, Takei K, Sakima N, Myagmar BE, Taira K, Uezato H, Ogawa Y, Kariya K (Apr 2004). "Mitogen-activated protein kinase kinase kinase kinase 4 as a putative effector of Rap2 to activate the c-Jun N-terminal kinase". The Journal of Biological Chemistry. 279 (16): 15711–4. doi:10.1074/jbc.C300542200. PMID 14966141.
• Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP (Aug 2004). "Large-scale characterization of HeLa cell nuclear phosphoproteins". Proceedings of the National Academy of Sciences of the United States of America. 101 (33): 12130–5. doi:10.1073/pnas.0404720101. PMC 514446. PMID 15302935.
• Ballif BA, Villén J, Beausoleil SA, Schwartz D, Gygi SP (Nov 2004). "Phosphoproteomic analysis of the developing mouse brain". Molecular & Cellular Proteomics. 3 (11): 1093–101. doi:10.1074/mcp.M400085-MCP200. PMID 15345747.
• Collins CS, Hong J, Sapinoso L, Zhou Y, Liu Z, Micklash K, Schultz PG, Hampton GM (Mar 2006). "A small interfering RNA screen for modulators of tumor cell motility identifies MAP4K4 as a promigratory kinase". Proceedings of the National Academy of Sciences of the United States of America. 103 (10): 3775–80. doi:10.1073/pnas.0600040103. PMC 1383649. PMID 16537454.
• Wissing J, Jänsch L, Nimtz M, Dieterich G, Hornberger R, Kéri G, Wehland J, Daub H (Mar 2007). "Proteomics analysis of protein kinases by target class-selective prefractionation and tandem mass spectrometry". Molecular & Cellular Proteomics. 6 (3): 537–47. doi:10.1074/mcp.T600062-MCP200. PMID 17192257.