Mitogen Activated Protein (MAP) kinase kinase kinase (MAPKKK,[1]MKKK,[2]M3K,[3] or, MAP3K[4]) is a serine/threonine-specific protein kinase which acts upon MAP kinase kinase. Subsequently, MAP kinase kinase activates MAP kinase. Several types of MAPKKK can exist but are mainly characterized by the MAP kinases they activate. MAPKKKs are stimulated by a large range of stimuli, primarily environmental and intracellular stressors. MAPKKK is responsible for various cell functions such as cell proliferation, cell differentiation, and apoptosis. The duration and intensity of signals determine which pathway ensues. Additionally, the use of protein scaffolds helps to place the MAPKKK in close proximity with its substrate to allow for a reaction.[5] Lastly, because MAPKKK is involved in a series of several pathways, it has been used as a therapeutic target for cancer, amyloidosis, and neurodegenerative diseases. In humans, there are at least 19 genes which encode MAP kinase kinase kinases:
Several classes of MAPKKK exist, and all of them are upstream of MAP kinases. There are three main classes of MAP Kinases and are regulated by their respective MAPKKKs. These MAP kinases include the extracellular regulated kinases (ERKs), the c-Jun N-terminal Kinases (JNKs), and the p38 MAP kinase. The ERKs are regulated by the Raf family of MAPKKKs and are responsible for cell growth, differentiation, and meiosis. Perhaps the best characterized MAP3K are the members of the oncogenic RAF family (RAF1, BRAF, ARAF), which are effectors of mitogenic ras signaling and which activate the ERK1/2 (MAPK3/MAPK1) pathway, through activation of MEK1(MAP2K1) and MEK2(MAP2K2). The JNKs are regulated by the MEKK 1/4, MLK 2/3, and ASK 1 MAPKKKs. The p38 MAPK is regulated by MEKK 1-4 and TAO 1/2 families of MAPKKKs and is responsible for inflammation, apoptosis, cell differentiation, and cell cycle regulation. The determination for what cascade is followed is based upon the type of signal, the strength of binding, and the length of binding.[5][9]
MEKK1 activates MAPK8/JNK by phosphorylation of its activator SEK1(MAP2K4).[10]
MAP3K7(TAK1) participates in regulation of transcription by transforming growth factor-beta (TGF-beta).[12]
Activation and deactivation of MAPKKKedit
The most upstream stimuli that activate MAPKKK is either stress or growth factors. This includes mitogens, inflammatory cytokines, ER stress, oxidative stress, UV radiation, and DNA damage. Most MAPKKKs are activated through GPCR's where the signal from the stimuli binds to the GPCR and the GTPase activity of the g-protein activates the downstream MAPKKK. Other mechanisms for MAPKKK do exist. For instance, the MAPKKK ASK-1 is activated by a receptor-tyrosine kinase specific for a tumor necrosis factor. Since MAPKKK are activated through the addition of a phosphates group on a serine/threonine residue, they are deactivated by a phosphatase. A common phosphatase used in ASK-1 regulation is PP5.[13] MAPKKKs contain a docking domain which is different from their active site that allows them to contact another substrate. Additionally, several scaffolds are used in the MAPKKK cascade in order to ensure that a specific cascade is used. These scaffolds have a binding site for the MAPKKK, MAPKK, and MAPK, ensuring that the signal occurs rapidly.[9]
Clinical significanceedit
Because MAPKKKs are involved in a wide range of cell responses occurring both in the cytoplasm and the nucleus, a mutation in these genes can cause several diseases. Over-expression of the MAPKKK upstream of the ERK 1/2 MAPK and an increase in epidermal growth factor receptor (EGFR) can lead to tumor formation, such as triple negative breast cancer.[14] A mutation in the JNK or p38 family of MAPK or their MAPKKK upstream precursors can result in Alzheimer's disease. This is also seen when there is too much oxidative stress in the brain, causing these MAPKs to undergo more apoptosis and destroy brain cells. MLK, a type of MAPKKK, are associated with Parkinson's disease and inhibitors to the MLK proteins have been shown to treat Parkinson's disease. The MAPKKK pathways and specifically the over-expression of cascades of JNK and p38 are also involved in Crohn's disease and polycystic kidney disease. Inhibitors of these pathways help in treating the symptoms of the diseases.[15]
Imagesedit
MAPK pathway. Many of the MAP3K's here are labelled by their alternative names.
^ "Global Identification, Classification, and Expression Analysis of MAPKKK genes: Functional Characterization of MdRaf5 Reveals Evolution and Drought-Responsive Profile in Apple". Scientific Reports. 7. 2017. doi:10.1038/s41598-017-13627-2. PMC5647345. 13511.
^ "MAPK kinase kinases (MKKKs) as a target class for small-molecule inhibition to modulate signaling networks and gene expression". Current Opinion in Chemical Biology. June 2005. doi:10.1016/j.cbpa.2005.04.004. PMID 15939336.
^ "MAP3Kinase-dependent SnRK2-kinase activation is required for abscisic acid signal transduction and rapid osmotic stress response". Nature Communications. 11. 2020. doi:10.1038/s41467-019-13875-y. PMC6940395. 12.
^ Bruce D. Cuevas (2014). "Mitogen-Activated Protein Kinase Kinase Kinases". Encyclopedia of Cancer. doi:10.1007/978-3-662-46875-3_7192.
^ abMorrison, Deborah K. (2012-11-01). "MAP Kinase Pathways". Cold Spring Harbor Perspectives in Biology. 4 (11): a011254. doi:10.1101/cshperspect.a011254. ISSN 1943-0264. PMC3536342. PMID 23125017.
^ Yan M, Dai T, Deak JC, Kyriakis JM, Zon LI, Woodgett JR, Templeton DJ (1994). "Activation of stress-activated protein kinase by MEKK1 phosphorylation of its activator SEK1". Nature. 372 (6508): 798–800. Bibcode:1994Natur.372..798Y. doi:10.1038/372798a0. PMID 7997270. S2CID 4369739.
^ Ellinger-Ziegelbauer H, Brown K, Kelly K, Siebenlist U (January 1997). "Direct activation of the stress-activated protein kinase (SAPK) and extracellular signal-regulated protein kinase (ERK) pathways by an inducible mitogen-activated protein Kinase/ERK kinase kinase 3 (MEKK) derivative". The Journal of Biological Chemistry. 272 (5): 2668–74. doi:10.1074/jbc.272.5.2668. PMID 9006902.
^ Yamaguchi K, Shirakabe K, Shibuya H, Irie K, Oishi I, Ueno N, Taniguchi T, Nishida E, Matsumoto K (December 1995). "Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction". Science. 270 (5244): 2008–11. Bibcode:1995Sci...270.2008Y. doi:10.1126/science.270.5244.2008. PMID 8533096. S2CID 46600809.
^Takeda, Kohsuke; Matsuzawa, Atsushi; Nishitoh, Hideki; Ichijo, Hidenori (February 2003). "Roles of MAPKKK ASK1 in stress-induced cell death". Cell Structure and Function. 28 (1): 23–29. doi:10.1247/csf.28.23. ISSN 0386-7196. PMID 12655147.
^Jiang, Weihua; Wang, Xiaowen; Zhang, Chenguang; Xue, Laiti; Yang, Liang (March 2020). "Expression and clinical significance of MAPK and EGFR in triple-negative breast cancer". Oncology Letters. 19 (3): 1842–1848. doi:10.3892/ol.2020.11274. ISSN 1792-1074. PMC7038935. PMID 32194678.
^Kim, Eun Kyung; Choi, Eui-Ju (2010-04-01). "Pathological roles of MAPK signaling pathways in human diseases". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1802 (4): 396–405. doi:10.1016/j.bbadis.2009.12.009. ISSN 0925-4439. PMID 20079433.
External linksedit
MAP+Kinase+Kinase+Kinases at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
kinase, kinase, kinase, mkkk, redirects, here, other, uses, mkkk, mitogen, activated, protein, kinase, kinase, kinase, mapkkk, mkkk, map3k, serine, threonine, specific, protein, kinase, which, acts, upon, kinase, kinase, subsequently, kinase, kinase, activates. mkkk redirects here For other uses see MKKK Mitogen Activated Protein MAP kinase kinase kinase MAPKKK 1 MKKK 2 M3K 3 or MAP3K 4 is a serine threonine specific protein kinase which acts upon MAP kinase kinase Subsequently MAP kinase kinase activates MAP kinase Several types of MAPKKK can exist but are mainly characterized by the MAP kinases they activate MAPKKKs are stimulated by a large range of stimuli primarily environmental and intracellular stressors MAPKKK is responsible for various cell functions such as cell proliferation cell differentiation and apoptosis The duration and intensity of signals determine which pathway ensues Additionally the use of protein scaffolds helps to place the MAPKKK in close proximity with its substrate to allow for a reaction 5 Lastly because MAPKKK is involved in a series of several pathways it has been used as a therapeutic target for cancer amyloidosis and neurodegenerative diseases In humans there are at least 19 genes which encode MAP kinase kinase kinases MAP3K1 aka MEKK1 MAP3K2 aka MEKK2 MAP3K3 aka MEKK3 MAP3K4 aka MEKK4 MAP3K5 aka ASK1 MAP3K6 aka ASK2 MAP3K7 aka MEKK7 aka TAK1 MAP3K8 aka TPL2 or Tpl2 MAP3K9 MAP3K10 MAP3K11 aka MEKK11 aka MLK3 MAP3K12 aka MUK MAP3K13 aka LZK MAP3K14 MAP3K15 MAP3K16 aka TAO1 or TAOK1 MAP3K17 aka TAO2 or TAOK2 MAP3K18 aka TAO3 or TAOK3 6 7 8 RAF1 BRAF ARAF ZAK aka MLTK Mitogen activated protein kinase kinase kinaseIdentifiersEC no 2 7 11 25CAS no 146702 84 3DatabasesIntEnzIntEnz viewBRENDABRENDA entryExPASyNiceZyme viewKEGGKEGG entryMetaCycmetabolic pathwayPRIAMprofilePDB structuresRCSB PDB PDBe PDBsumSearchPMCarticlesPubMedarticlesNCBIproteins Contents 1 Classes of MAPKKK and their functions 2 Activation and deactivation of MAPKKK 3 Clinical significance 4 Images 5 See also 6 References 7 External linksClasses of MAPKKK and their functions editSeveral classes of MAPKKK exist and all of them are upstream of MAP kinases There are three main classes of MAP Kinases and are regulated by their respective MAPKKKs These MAP kinases include the extracellular regulated kinases ERKs the c Jun N terminal Kinases JNKs and the p38 MAP kinase The ERKs are regulated by the Raf family of MAPKKKs and are responsible for cell growth differentiation and meiosis Perhaps the best characterized MAP3K are the members of the oncogenic RAF family RAF1 BRAF ARAF which are effectors of mitogenic ras signaling and which activate the ERK1 2 MAPK3 MAPK1 pathway through activation of MEK1 MAP2K1 and MEK2 MAP2K2 The JNKs are regulated by the MEKK 1 4 MLK 2 3 and ASK 1 MAPKKKs The p38 MAPK is regulated by MEKK 1 4 and TAO 1 2 families of MAPKKKs and is responsible for inflammation apoptosis cell differentiation and cell cycle regulation The determination for what cascade is followed is based upon the type of signal the strength of binding and the length of binding 5 9 MEKK1 activates MAPK8 JNK by phosphorylation of its activator SEK1 MAP2K4 10 MAP3K3 directly regulates the MAPK8 JNK and extracellular signal regulated protein kinase ERK pathways by activating SEK and MEK1 2 respectively it does not regulate the p38 pathway 11 MAP3K7 TAK1 participates in regulation of transcription by transforming growth factor beta TGF beta 12 Activation and deactivation of MAPKKK editThe most upstream stimuli that activate MAPKKK is either stress or growth factors This includes mitogens inflammatory cytokines ER stress oxidative stress UV radiation and DNA damage Most MAPKKKs are activated through GPCR s where the signal from the stimuli binds to the GPCR and the GTPase activity of the g protein activates the downstream MAPKKK Other mechanisms for MAPKKK do exist For instance the MAPKKK ASK 1 is activated by a receptor tyrosine kinase specific for a tumor necrosis factor Since MAPKKK are activated through the addition of a phosphates group on a serine threonine residue they are deactivated by a phosphatase A common phosphatase used in ASK 1 regulation is PP5 13 MAPKKKs contain a docking domain which is different from their active site that allows them to contact another substrate Additionally several scaffolds are used in the MAPKKK cascade in order to ensure that a specific cascade is used These scaffolds have a binding site for the MAPKKK MAPKK and MAPK ensuring that the signal occurs rapidly 9 Clinical significance editBecause MAPKKKs are involved in a wide range of cell responses occurring both in the cytoplasm and the nucleus a mutation in these genes can cause several diseases Over expression of the MAPKKK upstream of the ERK 1 2 MAPK and an increase in epidermal growth factor receptor EGFR can lead to tumor formation such as triple negative breast cancer 14 A mutation in the JNK or p38 family of MAPK or their MAPKKK upstream precursors can result in Alzheimer s disease This is also seen when there is too much oxidative stress in the brain causing these MAPKs to undergo more apoptosis and destroy brain cells MLK a type of MAPKKK are associated with Parkinson s disease and inhibitors to the MLK proteins have been shown to treat Parkinson s disease The MAPKKK pathways and specifically the over expression of cascades of JNK and p38 are also involved in Crohn s disease and polycystic kidney disease Inhibitors of these pathways help in treating the symptoms of the diseases 15 Images edit nbsp MAPK pathway Many of the MAP3K s here are labelled by their alternative names See also editMAP kinase MAP kinase kinase MAP kinase kinase kinase kinase List of unusual biological namesReferences edit Global Identification Classification and Expression Analysis of MAPKKK genes Functional Characterization of MdRaf5 Reveals Evolution and Drought Responsive Profile in Apple Scientific Reports 7 2017 doi 10 1038 s41598 017 13627 2 PMC 5647345 13511 MAPK kinase kinases MKKKs as a target class for small molecule inhibition to modulate signaling networks and gene expression Current Opinion in Chemical Biology June 2005 doi 10 1016 j cbpa 2005 04 004 PMID 15939336 MAP3Kinase dependent SnRK2 kinase activation is required for abscisic acid signal transduction and rapid osmotic stress response Nature Communications 11 2020 doi 10 1038 s41467 019 13875 y PMC 6940395 12 Bruce D Cuevas 2014 Mitogen Activated Protein Kinase Kinase Kinases Encyclopedia of Cancer doi 10 1007 978 3 662 46875 3 7192 a b Morrison Deborah K 2012 11 01 MAP Kinase Pathways Cold Spring Harbor Perspectives in Biology 4 11 a011254 doi 10 1101 cshperspect a011254 ISSN 1943 0264 PMC 3536342 PMID 23125017 TAOK3 TAO kinase 3 Homo sapiens human Gene NCBI www ncbi nlm nih gov Retrieved 2022 01 04 TAOK3 Gene GeneCards TAOK3 Protein TAOK3 Antibody www genecards org Retrieved 2022 01 04 TAOK3 Serine threonine protein kinase TAO3 Homo sapiens Human TAOK3 gene amp protein www uniprot org Retrieved 2022 01 04 a b Qi Maosong Elion Elaine A 2005 08 15 MAP kinase pathways Journal of Cell Science 118 16 3569 3572 doi 10 1242 jcs 02470 ISSN 0021 9533 PMID 16105880 Yan M Dai T Deak JC Kyriakis JM Zon LI Woodgett JR Templeton DJ 1994 Activation of stress activated protein kinase by MEKK1 phosphorylation of its activator SEK1 Nature 372 6508 798 800 Bibcode 1994Natur 372 798Y doi 10 1038 372798a0 PMID 7997270 S2CID 4369739 Ellinger Ziegelbauer H Brown K Kelly K Siebenlist U January 1997 Direct activation of the stress activated protein kinase SAPK and extracellular signal regulated protein kinase ERK pathways by an inducible mitogen activated protein Kinase ERK kinase kinase 3 MEKK derivative The Journal of Biological Chemistry 272 5 2668 74 doi 10 1074 jbc 272 5 2668 PMID 9006902 Yamaguchi K Shirakabe K Shibuya H Irie K Oishi I Ueno N Taniguchi T Nishida E Matsumoto K December 1995 Identification of a member of the MAPKKK family as a potential mediator of TGF beta signal transduction Science 270 5244 2008 11 Bibcode 1995Sci 270 2008Y doi 10 1126 science 270 5244 2008 PMID 8533096 S2CID 46600809 Takeda Kohsuke Matsuzawa Atsushi Nishitoh Hideki Ichijo Hidenori February 2003 Roles of MAPKKK ASK1 in stress induced cell death Cell Structure and Function 28 1 23 29 doi 10 1247 csf 28 23 ISSN 0386 7196 PMID 12655147 Jiang Weihua Wang Xiaowen Zhang Chenguang Xue Laiti Yang Liang March 2020 Expression and clinical significance of MAPK and EGFR in triple negative breast cancer Oncology Letters 19 3 1842 1848 doi 10 3892 ol 2020 11274 ISSN 1792 1074 PMC 7038935 PMID 32194678 Kim Eun Kyung Choi Eui Ju 2010 04 01 Pathological roles of MAPK signaling pathways in human diseases Biochimica et Biophysica Acta BBA Molecular Basis of Disease 1802 4 396 405 doi 10 1016 j bbadis 2009 12 009 ISSN 0925 4439 PMID 20079433 External links editMAP Kinase Kinase Kinases at the U S National Library of Medicine Medical Subject Headings MeSH EC 2 7 11 25 Portal nbsp Biology Retrieved from https en wikipedia org w index php title MAP kinase kinase kinase amp oldid 1193148683, wikipedia, wiki, book, books, library,
