Mitogen-activated protein kinase kinase kinase kinase 2

Details

Name
Mitogen-activated protein kinase kinase kinase kinase 2
Synonyms
  • 2.7.11.1
  • B lymphocyte serine/threonine-protein kinase
  • GC kinase
  • GCK
  • Germinal center kinase
  • MAPK/ERK kinase kinase kinase 2
  • MEK kinase kinase 2
  • MEKKK 2
  • Rab8-interacting protein
  • RAB8IP
Gene Name
MAP4K2
Organism
Humans
Amino acid sequence
>lcl|BSEQ0051820|Mitogen-activated protein kinase kinase kinase kinase 2
MALLRDVSLQDPRDRFELLQRVGAGTYGDVYKARDTVTSELAAVKIVKLDPGDDISSLQQ
EITILRECRHPNVVAYIGSYLRNDRLWICMEFCGGGSLQEIYHATGPLEERQIAYVCREA
LKGLHHLHSQGKIHRDIKGANLLLTLQGDVKLADFGVSGELTASVAKRRSFIGTPYWMAP
EVAAVERKGGYNELCDVWALGITAIELGELQPPLFHLHPMRALMLMSKSSFQPPKLRDKT
RWTQNFHHFLKLALTKNPKKRPTAEKLLQHPFTTQQLPRALLTQLLDKASDPHLGTPSPE
DCELETYDMFPDTIHSRGQHGPAERTPSEIQFHQVKFGAPRRKETDPLNEPWEEEWTLLG
KEELSGSLLQSVQEALEERSLTIRSASEFQELDSPDDTMGTIKRAPFLGPLPTDPPAEEP
LSSPPGTLPPPPSGPNSSPLLPTAWATMKQREDPERSSCHGLPPTPKVHMGACFSKVFNG
CPLRIHAAVTWIHPVTRDQFLVVGAEEGIYTLNLHELHEDTLEKLISHRCSWLYCVNNVL
LSLSGKSTHIWAHDLPGLFEQRRLQQQVPLSIPTNRLTQRIIPRRFALSTKIPDTKGCLQ
CRVVRNPYTGATFLLAALPTSLLLLQWYEPLQKFLLLKNFSSPLPSPAGMLEPLVLDGKE
LPQVCVGAEGPEGPGCRVLFHVLPLEAGLTPDILIPPEGIPGSAQQVIQVDRDTILVSFE
RCVRIVNMQGEPTATLAPELTFDFPIETVVCLQDSVLAFWSHGMQGRSLDTNEVTQEITD
ETRIFRVLGAHRDIILESIPTDNPEAHSNLYILTGHQSTY
Number of residues
820
Molecular Weight
91555.075
Theoretical pI
Not Available
GO Classification
Functions
ATP binding / MAP kinase kinase kinase kinase activity / mitogen-activated protein kinase kinase kinase binding / protein serine/threonine kinase activity
Processes
activation of JUN kinase activity / immune response / innate immune response / intracellular signal transduction / JNK cascade / positive regulation of JNK cascade / protein phosphorylation / regulation of apoptotic process / regulation of mitotic cell cycle / vesicle targeting
Components
basolateral plasma membrane / cytoplasm / Golgi membrane
General Function
Serine/threonine-protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Acts as a MAPK kinase kinase kinase (MAP4K) and is an upstream activator of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway and to a lesser extent of the p38 MAPKs signaling pathway. Required for the efficient activation of JNKs by TRAF6-dependent stimuli, including pathogen-associated molecular patterns (PAMPs) such as polyinosine-polycytidine (poly(IC)), lipopolysaccharides (LPS), lipid A, peptidoglycan (PGN), or bacterial flagellin. To a lesser degree, IL-1 and engagement of CD40 also stimulate MAP4K2-mediated JNKs activation. The requirement for MAP4K2/GCK is most pronounced for LPS signaling, and extends to LPS stimulation of c-Jun phosphorylation and induction of IL-8. Enhances MAP3K1 oligomerization, which may relieve N-terminal mediated MAP3K1 autoinhibition and lead to activation following autophosphorylation. Mediates also the SAP/JNK signaling pathway and the p38 MAPKs signaling pathway through activation of the MAP3Ks MAP3K10/MLK2 and MAP3K11/MLK3. May play a role in the regulation of vesicle targeting or fusion. regulation of vesicle targeting or fusion.
Specific Function
Atp binding
Pfam Domain Function
Transmembrane Regions
Not Available
Cellular Location
Cytoplasm
Gene sequence
>lcl|BSEQ0051821|Mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2)
ATGGCGCTGCTGCGGGATGTGTCGCTGCAGGACCCGCGGGACCGCTTCGAGCTGCTGCAG
CGCGTGGGGGCCGGGACCTATGGCGACGTCTACAAGGCCCGCGACACGGTCACGTCCGAA
CTGGCCGCCGTGAAGATAGTCAAGCTAGACCCAGGGGACGACATCAGCTCCCTCCAGCAG
GAAATCACCATCCTGCGTGAGTGCCGCCACCCCAATGTGGTGGCCTACATTGGCAGCTAC
CTCAGGAATGACCGCTTGTGGATCTGCATGGAGTTCTGCGGAGGGGGCTCCCTGCAGGAG
ATTTACCATGCCACTGGGCCCCTGGAGGAGCGGCAGATTGCCTACGTCTGCCGAGAGGCA
CTGAAGGGGCTCCACCACCTGCATTCTCAGGGGAAGATCCACAGAGACATCAAGGGAGCC
AACCTTCTCCTCACTCTCCAGGGAGATGTCAAACTGGCTGACTTTGGGGTGTCAGGCGAG
CTGACAGCGTCTGTGGCCAAGAGGAGGTCTTTCATTGGGACTCCCTACTGGATGGCTCCC
GAGGTGGCTGCTGTGGAGCGCAAAGGTGGCTACAATGAGCTATGTGACGTCTGGGCCCTG
GGCATCACTGCCATTGAGCTGGGCGAGCTGCAGCCCCCTCTGTTCCACCTGCACCCCATG
AGGGCCCTGATGCTCATGTCGAAGAGCAGCTTCCAGCCGCCCAAACTGAGAGATAAGACT
CGCTGGACCCAGAATTTCCACCACTTTCTCAAACTGGCCCTGACCAAGAATCCTAAGAAG
AGGCCGACAGCAGAGAAGCTCCTGCAGCACCCGTTCACGACTCAGCAGCTCCCTCGGGCC
CTCCTCACACAGCTGCTGGACAAAGCCAGTGACCCTCATCTGGGGACCCCCTCCCCTGAG
GACTGTGAGCTGGAGACCTATGACATGTTTCCAGACACCATTCACTCCCGGGGGCAGCAC
GGCCCAGCCGAGAGGACCCCCTCGGAGATCCAGTTTCACCAGGTGAAATTTGGCGCCCCA
CGCAGGAAGGAAACTGACCCACTGAATGAGCCGTGGGAGGAAGAGTGGACACTACTGGGA
AAGGAAGAGTTGAGTGGGAGCCTGCTGCAGTCGGTCCAGGAGGCCCTGGAGGAAAGGAGT
CTGACTATTCGGTCAGCCTCAGAATTCCAGGAGCTGGACTCCCCAGACGATACCATGGGA
ACCATCAAGCGGGCCCCGTTCCTAGGGCCACTCCCCACTGACCCTCCAGCAGAGGAGCCT
CTGTCCAGTCCCCCAGGAACCCTGCCCCCACCTCCTTCAGGCCCCAACAGCTCCCCACTG
CTGCCCACGGCCTGGGCCACCATGAAGCAGCGGGAGGATCCTGAGAGGTCATCCTGCCAC
GGGCTCCCCCCAACTCCCAAGGTGCATATGGGCGCCTGCTTCTCCAAGGTCTTCAATGGC
TGCCCCCTGCGGATCCACGCTGCTGTCACCTGGATTCACCCTGTTACTCGGGACCAGTTC
CTGGTGGTAGGGGCCGAGGAAGGCATCTACACACTCAACCTGCATGAACTGCATGAGGAT
ACGCTGGAGAAGCTGATTTCACATCGCTGCTCCTGGCTCTACTGCGTGAACAACGTGCTG
CTGTCACTCTCAGGGAAATCCACGCACATCTGGGCCCATGACCTCCCAGGCCTGTTTGAG
CAGCGGAGGCTACAGCAACAGGTTCCCCTCTCCATCCCCACCAACCGCCTCACCCAGCGC
ATCATCCCCAGGCGCTTTGCTCTGTCCACCAAGATTCCTGACACCAAAGGCTGCTTGCAG
TGTCGTGTGGTGCGGAACCCCTACACGGGTGCCACCTTCCTGCTGGCCGCCCTGCCCACC
AGCCTGCTCCTGCTGCAGTGGTATGAGCCGCTGCAGAAGTTTCTGCTGCTGAAGAACTTC
TCCAGCCCTCTGCCCAGCCCAGCTGGGATGCTGGAGCCGCTGGTGCTGGATGGGAAGGAG
CTGCCGCAGGTGTGTGTTGGGGCCGAGGGGCCTGAGGGGCCCGGCTGCCGCGTCCTGTTC
CATGTCCTGCCCCTGGAGGCTGGCCTGACGCCCGACATCCTCATCCCACCTGAGGGGATC
CCAGGCTCGGCCCAGCAGGTGATCCAGGTGGACAGGGACACAATCCTAGTCAGCTTTGAA
CGCTGTGTGAGGATTGTCAACATGCAGGGCGAGCCCACGGCCACACTGGCACCTGAGCTG
ACCTTTGATTTCCCCATCGAGACTGTGGTGTGCCTGCAGGACAGTGTGCTGGCCTTCTGG
AGCCATGGGATGCAAGGCCGAAGCCTGGATACCAATGAGGTGACCCAGGAGATCACAGAT
GAAACAAGGATCTTCCGAGTGCTTGGGGCCCACAGAGACATCATCCTGGAGAGCATTCCC
ACTGACAACCCAGAGGCGCACAGCAACCTCTACATCCTCACGGGCCACCAGAGCACCTAC
TAA
Chromosome Location
11
Locus
11q13.1
External Identifiers
ResourceLink
UniProtKB IDQ12851
UniProtKB Entry NameM4K2_HUMAN
HGNC IDHGNC:6864
General References
  1. Taylor TD, Noguchi H, Totoki Y, Toyoda A, Kuroki Y, Dewar K, Lloyd C, Itoh T, Takeda T, Kim DW, She X, Barlow KF, Bloom T, Bruford E, Chang JL, Cuomo CA, Eichler E, FitzGerald MG, Jaffe DB, LaButti K, Nicol R, Park HS, Seaman C, Sougnez C, Yang X, Zimmer AR, Zody MC, Birren BW, Nusbaum C, Fujiyama A, Hattori M, Rogers J, Lander ES, Sakaki Y: Human chromosome 11 DNA sequence and analysis including novel gene identification. Nature. 2006 Mar 23;440(7083):497-500. [Article]
  2. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [Article]
  3. Katz P, Whalen G, Kehrl JH: Differential expression of a novel protein kinase in human B lymphocytes. Preferential localization in the germinal center. J Biol Chem. 1994 Jun 17;269(24):16802-9. [Article]
  4. Pombo CM, Kehrl JH, Sanchez I, Katz P, Avruch J, Zon LI, Woodgett JR, Force T, Kyriakis JM: Activation of the SAPK pathway by the human STE20 homologue germinal centre kinase. Nature. 1995 Oct 26;377(6551):750-4. [Article]
  5. Yuasa T, Ohno S, Kehrl JH, Kyriakis JM: Tumor necrosis factor signaling to stress-activated protein kinase (SAPK)/Jun NH2-terminal kinase (JNK) and p38. Germinal center kinase couples TRAF2 to mitogen-activated protein kinase/ERK kinase kinase 1 and SAPK while receptor interacting protein associates with a mitogen-activated protein kinase kinase kinase upstream of MKK6 and p38. J Biol Chem. 1998 Aug 28;273(35):22681-92. [Article]
  6. Chadee DN, Yuasa T, Kyriakis JM: Direct activation of mitogen-activated protein kinase kinase kinase MEKK1 by the Ste20p homologue GCK and the adapter protein TRAF2. Mol Cell Biol. 2002 Feb;22(3):737-49. [Article]
  7. Zhong J, Kyriakis JM: Germinal center kinase is required for optimal Jun N-terminal kinase activation by Toll-like receptor agonists and is regulated by the ubiquitin proteasome system and agonist-induced, TRAF6-dependent stabilization. Mol Cell Biol. 2004 Oct;24(20):9165-75. [Article]
  8. Zhong J, Kyriakis JM: Dissection of a signaling pathway by which pathogen-associated molecular patterns recruit the JNK and p38 MAPKs and trigger cytokine release. J Biol Chem. 2007 Aug 17;282(33):24246-54. Epub 2007 Jun 21. [Article]
  9. Kyriakis JM: Signaling by the germinal center kinase family of protein kinases. J Biol Chem. 1999 Feb 26;274(9):5259-62. [Article]
  10. Dan I, Watanabe NM, Kusumi A: The Ste20 group kinases as regulators of MAP kinase cascades. Trends Cell Biol. 2001 May;11(5):220-30. [Article]
  11. Dephoure N, Zhou C, Villen J, Beausoleil SA, Bakalarski CE, Elledge SJ, Gygi SP: A quantitative atlas of mitotic phosphorylation. Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10762-7. doi: 10.1073/pnas.0805139105. Epub 2008 Jul 31. [Article]
  12. Oppermann FS, Gnad F, Olsen JV, Hornberger R, Greff Z, Keri G, Mann M, Daub H: Large-scale proteomics analysis of the human kinome. Mol Cell Proteomics. 2009 Jul;8(7):1751-64. doi: 10.1074/mcp.M800588-MCP200. Epub 2009 Apr 15. [Article]
  13. Mayya V, Lundgren DH, Hwang SI, Rezaul K, Wu L, Eng JK, Rodionov V, Han DK: Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions. Sci Signal. 2009 Aug 18;2(84):ra46. doi: 10.1126/scisignal.2000007. [Article]
  14. Zhou H, Di Palma S, Preisinger C, Peng M, Polat AN, Heck AJ, Mohammed S: Toward a comprehensive characterization of a human cancer cell phosphoproteome. J Proteome Res. 2013 Jan 4;12(1):260-71. doi: 10.1021/pr300630k. Epub 2012 Dec 18. [Article]
  15. Bian Y, Song C, Cheng K, Dong M, Wang F, Huang J, Sun D, Wang L, Ye M, Zou H: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J Proteomics. 2014 Jan 16;96:253-62. doi: 10.1016/j.jprot.2013.11.014. Epub 2013 Nov 22. [Article]

Drug Relations

Drug Relations
DrugBank IDNameDrug groupPharmacological action?ActionsDetails
DB12010Fostamatinibapproved, investigationalunknowninhibitorDetails