MAP4K4

Mitogen-activated protein kinase kinase kinase kinase 4
Crystal Structure of MAP4K4. PDB entry 4obo​[1]
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 4OBO​, 4OBP​, 4OBQ​, 4RVT​, 4U43​, 4U44​, 4U45​
Identifiers
Symbols	MAP4K4 ; FLH21957; HEL-S-31; HGK; MEKKK4; NIK
External IDs	OMIM: 604666 MGI: 1349394 HomoloGene: 7442 ChEMBL: 6166 GeneCards: MAP4K4 Gene
EC number	2.7.11.1
Gene ontology Molecular function • creatine kinase activity • protein serine/threonine kinase activity • protein binding • ATP binding • MAP kinase kinase kinase kinase activity Cellular component • cytoplasm Biological process • MAPK cascade • protein phosphorylation • regulation of mitotic cell cycle • microvillus assembly • stress-activated protein kinase signaling cascade • activation of protein kinase activity • intracellular signal transduction • negative regulation of apoptotic process • regulation of JNK cascade • neuron projection morphogenesis 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_001252200
RefSeq (protein)	NP_001229488	NP_001239129
Location (UCSC)	Chr 2: 101.7 – 101.89 Mb	Chr 1: 39.9 – 40.03 Mb
PubMed search

Mitogen-activated protein kinase kinase kinase kinase 4 is an enzyme that in humans is encoded by the MAP4K4 gene.^[2][3][4][5]

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.^[5] A recent study showed that MAP4K4 is a direct kinase of LATS1/2 and thus regulates the Hippo pathway effectors YAP and TAZ. ^[6][7]

Interactions

MAP4K4 has been shown to interact with NCK1^[4] and CD29.^[8]

References

1. Crawford, T. D.; Ndubaku, C. O.; Chen, H; Boggs, J. W.; Bravo, B. J.; Delatorre, K; Giannetti, A. M.; Gould, S. E.; Harris, S. F.; Magnuson, S. R.; McNamara, E; Murray, L. J.; Nonomiya, J; Sambrone, A; Schmidt, S; Smyczek, T; Stanley, M; Vitorino, P; Wang, L; West, K; Wu, P; Ye, W (2014). "Discovery of Selective 4-Amino-pyridopyrimidine Inhibitors of MAP4K4 Using Fragment-Based Lead Identification and Optimization". Journal of Medicinal Chemistry 57 (8): 3484–93. doi:10.1021/jm500155b. PMID 24673130.
2. 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.
3. 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.
4. 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.
5. "Entrez Gene: MAP4K4 mitogen-activated protein kinase kinase kinase kinase 4".
6. 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.
7. 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.
8. 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.