RAF/MAP kinase cascade (Homo sapiens)

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Description

The MAP kinase cascade describes a sequence of phosphorylation events involving serine/threonine-specific protein kinases. Used by various signal transduction pathways, this cascade constitutes a common 'module' in the transmission of an extracellular signal into the nucleus.Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=109869

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Eisenhardt AE, Olbrich H, Röring M, Janzarik W, Anh TN, Cin H, Remke M, Witt H, Korshunov A, Pfister SM, Omran H, Brummer T.; ''Functional characterization of a BRAF insertion mutant associated with pilocytic astrocytoma.''; PubMed Europe PMC Scholia
Tran NH, Wu X, Frost JA.; ''B-Raf and Raf-1 are regulated by distinct autoregulatory mechanisms.''; PubMed Europe PMC Scholia
Weber CK, Slupsky JR, Kalmes HA, Rapp UR.; ''Active Ras induces heterodimerization of cRaf and BRaf.''; PubMed Europe PMC Scholia
Zhang M, Jang H, Nussinov R.; ''The structural basis for Ras activation of PI3Kα lipid kinase.''; PubMed Europe PMC Scholia
Kikuchi A, Demo SD, Ye ZH, Chen YW, Williams LT.; ''ralGDS family members interact with the effector loop of ras p21.''; PubMed Europe PMC Scholia
Van Allen EM, Wagle N, Sucker A, Treacy DJ, Johannessen CM, Goetz EM, Place CS, Taylor-Weiner A, Whittaker S, Kryukov GV, Hodis E, Rosenberg M, McKenna A, Cibulskis K, Farlow D, Zimmer L, Hillen U, Gutzmer R, Goldinger SM, Ugurel S, Gogas HJ, Egberts F, Berking C, Trefzer U, Loquai C, Weide B, Hassel JC, Gabriel SB, Carter SL, Getz G, Garraway LA, Schadendorf D, Dermatologic Cooperative Oncology Group of Germany (DeCOG).; ''The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma.''; PubMed Europe PMC Scholia
Wakioka T, Sasaki A, Kato R, Shouda T, Matsumoto A, Miyoshi K, Tsuneoka M, Komiya S, Baron R, Yoshimura A.; ''Spred is a Sprouty-related suppressor of Ras signalling.''; PubMed Europe PMC Scholia
Wu LC.; ''Immunoglobulin E receptor signaling and asthma.''; PubMed Europe PMC Scholia
Hou XJ, Ni KM, Yang JM, Li XM.; ''Neuregulin 1/ErbB4 enhances synchronized oscillations of prefrontal cortex neurons via inhibitory synapses.''; PubMed Europe PMC Scholia
Voges D, Zwickl P, Baumeister W.; ''The 26S proteasome: a molecular machine designed for controlled proteolysis.''; PubMed Europe PMC Scholia
Torii S, Kusakabe M, Yamamoto T, Maekawa M, Nishida E.; ''Sef is a spatial regulator for Ras/MAP kinase signaling.''; PubMed Europe PMC Scholia
Hayes SD, Liu H, MacDonald E, Sanderson CM, Coulson JM, Clague MJ, Urbé S.; ''Direct and indirect control of mitogen-activated protein kinase pathway-associated components, BRAP/IMP E3 ubiquitin ligase and CRAF/RAF1 kinase, by the deubiquitylating enzyme USP15.''; PubMed Europe PMC Scholia
Lefloch R, Pouysségur J, Lenormand P.; ''Total ERK1/2 activity regulates cell proliferation.''; PubMed Europe PMC Scholia
Gysin S, Salt M, Young A, McCormick F.; ''Therapeutic strategies for targeting ras proteins.''; PubMed Europe PMC Scholia
Teis D, Taub N, Kurzbauer R, Hilber D, de Araujo ME, Erlacher M, Offterdinger M, Villunger A, Geley S, Bohn G, Klein C, Hess MW, Huber LA.; ''p14-MP1-MEK1 signaling regulates endosomal traffic and cellular proliferation during tissue homeostasis.''; PubMed Europe PMC Scholia
Lennartsson J, Rönnstrand L.; ''The stem cell factor receptor/c-Kit as a drug target in cancer.''; PubMed Europe PMC Scholia
Diaz B, Barnard D, Filson A, MacDonald S, King A, Marshall M.; ''Phosphorylation of Raf-1 serine 338-serine 339 is an essential regulatory event for Ras-dependent activation and biological signaling.''; PubMed Europe PMC Scholia
Elenius K, Paul S, Allison G, Sun J, Klagsbrun M.; ''Activation of HER4 by heparin-binding EGF-like growth factor stimulates chemotaxis but not proliferation.''; PubMed Europe PMC Scholia
Li Z, Mei Y, Liu X, Zhou M.; ''Neuregulin-1 only induces trans-phosphorylation between ErbB receptor heterodimer partners.''; PubMed Europe PMC Scholia
Luik RM, Wang B, Prakriya M, Wu MM, Lewis RS.; ''Oligomerization of STIM1 couples ER calcium depletion to CRAC channel activation.''; PubMed Europe PMC Scholia
Kiryushko D, Berezin V, Bock E.; ''Regulators of neurite outgrowth: role of cell adhesion molecules.''; PubMed Europe PMC Scholia
Ni CY, Murphy MP, Golde TE, Carpenter G.; ''gamma -Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase.''; PubMed Europe PMC Scholia
Nikolaev SI, Rimoldi D, Iseli C, Valsesia A, Robyr D, Gehrig C, Harshman K, Guipponi M, Bukach O, Zoete V, Michielin O, Muehlethaler K, Speiser D, Beckmann JS, Xenarios I, Halazonetis TD, Jongeneel CV, Stevenson BJ, Antonarakis SE.; ''Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma.''; PubMed Europe PMC Scholia
Krauthammer M, Kong Y, Bacchiocchi A, Evans P, Pornputtapong N, Wu C, McCusker JP, Ma S, Cheng E, Straub R, Serin M, Bosenberg M, Ariyan S, Narayan D, Sznol M, Kluger HM, Mane S, Schlessinger J, Lifton RP, Halaban R.; ''Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas.''; PubMed Europe PMC Scholia
Fu SM, Winchester RJ, Kunkel HG.; ''Occurrence of surface IgM, IgD, and free light chains of human lymphocytes.''; PubMed Europe PMC Scholia
Roskoski R.; ''RAF protein-serine/threonine kinases: structure and regulation.''; PubMed Europe PMC Scholia
Williams EJ, Furness J, Walsh FS, Doherty P.; ''Activation of the FGF receptor underlies neurite outgrowth stimulated by L1, N-CAM, and N-cadherin.''; PubMed Europe PMC Scholia
Saouaf SJ, Kut SA, Fargnoli J, Rowley RB, Bolen JB, Mahajan S.; ''Reconstitution of the B cell antigen receptor signaling components in COS cells.''; PubMed Europe PMC Scholia
Turnbull IR, Colonna M.; ''Activating and inhibitory functions of DAP12.''; PubMed Europe PMC Scholia
Panicker AK, Buhusi M, Thelen K, Maness PF.; ''Cellular signalling mechanisms of neural cell adhesion molecules.''; PubMed Europe PMC Scholia
Naresh A, Long W, Vidal GA, Wimley WC, Marrero L, Sartor CI, Tovey S, Cooke TG, Bartlett JM, Jones FE.; ''The ERBB4/HER4 intracellular domain 4ICD is a BH3-only protein promoting apoptosis of breast cancer cells.''; PubMed Europe PMC Scholia
Tzahar E, Levkowitz G, Karunagaran D, Yi L, Peles E, Lavi S, Chang D, Liu N, Yayon A, Wen D.; ''ErbB-3 and ErbB-4 function as the respective low and high affinity receptors of all Neu differentiation factor/heregulin isoforms.''; PubMed Europe PMC Scholia
Nel AE, Landreth GE, Goldschmidt-Clermont PJ, Tung HE, Galbraith RM.; ''Enhanced tyrosine phosphorylation in B lymphocytes upon complexing of membrane immunoglobulin.''; PubMed Europe PMC Scholia
Yeung K, Janosch P, McFerran B, Rose DW, Mischak H, Sedivy JM, Kolch W.; ''Mechanism of suppression of the Raf/MEK/extracellular signal-regulated kinase pathway by the raf kinase inhibitor protein.''; PubMed Europe PMC Scholia
Zhang BH, Guan KL.; ''Activation of B-Raf kinase requires phosphorylation of the conserved residues Thr598 and Ser601.''; PubMed Europe PMC Scholia
Pei D, Chen K, Liao H.; ''Targeting Ras with Macromolecules.''; PubMed Europe PMC Scholia
Adachi M, Fukuda M, Nishida E.; ''Two co-existing mechanisms for nuclear import of MAP kinase: passive diffusion of a monomer and active transport of a dimer.''; PubMed Europe PMC Scholia
Rio C, Buxbaum JD, Peschon JJ, Corfas G.; ''Tumor necrosis factor-alpha-converting enzyme is required for cleavage of erbB4/HER4.''; PubMed Europe PMC Scholia
Kim YJ, Sekiya F, Poulin B, Bae YS, Rhee SG.; ''Mechanism of B-cell receptor-induced phosphorylation and activation of phospholipase C-gamma2.''; PubMed Europe PMC Scholia
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Henry JR, Kaufman MD, Peng SB, Ahn YM, Caldwell TM, Vogeti L, Telikepalli H, Lu WP, Hood MM, Rutkoski TJ, Smith BD, Vogeti S, Miller D, Wise SC, Chun L, Zhang X, Zhang Y, Kays L, Hipskind PA, Wrobleski AD, Lobb KL, Clay JM, Cohen JD, Walgren JL, McCann D, Patel P, Clawson DK, Guo S, Manglicmot D, Groshong C, Logan C, Starling JJ, Flynn DL.; ''Discovery of 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (LY3009120) as a pan-RAF inhibitor with minimal paradoxical activation and activity against BRAF or RAS mutant tumor cells.''; PubMed Europe PMC Scholia
Genau HM, Huber J, Baschieri F, Akutsu M, Dötsch V, Farhan H, Rogov V, Behrends C.; ''CUL3-KBTBD6/KBTBD7 ubiquitin ligase cooperates with GABARAP proteins to spatially restrict TIAM1-RAC1 signaling.''; PubMed Europe PMC Scholia
Hou S, Suresh PS, Qi X, Lepp A, Mirza SP, Chen G.; ''p38γ Mitogen-activated protein kinase signals through phosphorylating its phosphatase PTPH1 in regulating ras protein oncogenesis and stress response.''; PubMed Europe PMC Scholia
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Roy M, Li Z, Sacks DB.; ''IQGAP1 binds ERK2 and modulates its activity.''; PubMed Europe PMC Scholia
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Kaushansky A, Gordus A, Budnik BA, Lane WS, Rush J, MacBeath G.; ''System-wide investigation of ErbB4 reveals 19 sites of Tyr phosphorylation that are unusually selective in their recruitment properties.''; PubMed Europe PMC Scholia
Kyriakis JM, Avruch J.; ''Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update.''; PubMed Europe PMC Scholia
Ishii N, Harada N, Joseph EW, Ohara K, Miura T, Sakamoto H, Matsuda Y, Tomii Y, Tachibana-Kondo Y, Iikura H, Aoki T, Shimma N, Arisawa M, Sowa Y, Poulikakos PI, Rosen N, Aoki Y, Sakai T.; ''Enhanced inhibition of ERK signaling by a novel allosteric MEK inhibitor, CH5126766, that suppresses feedback reactivation of RAF activity.''; PubMed Europe PMC Scholia
Ahearn I, Zhou M, Philips MR.; ''Posttranslational Modifications of RAS Proteins.''; PubMed Europe PMC Scholia
Edling CE, Hallberg B.; ''c-Kit--a hematopoietic cell essential receptor tyrosine kinase.''; PubMed Europe PMC Scholia
Zhang X, Ibrahimi OA, Olsen SK, Umemori H, Mohammadi M, Ornitz DM.; ''Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family.''; PubMed Europe PMC Scholia
Goetz CA, O'Neil JJ, Farrar MA.; ''Membrane localization, oligomerization, and phosphorylation are required for optimal raf activation.''; PubMed Europe PMC Scholia
Burack WR, Shaw AS.; ''Live Cell Imaging of ERK and MEK: simple binding equilibrium explains the regulated nucleocytoplasmic distribution of ERK.''; PubMed Europe PMC Scholia
Aqeilan RI, Donati V, Palamarchuk A, Trapasso F, Kaou M, Pekarsky Y, Sudol M, Croce CM.; ''WW domain-containing proteins, WWOX and YAP, compete for interaction with ErbB-4 and modulate its transcriptional function.''; PubMed Europe PMC Scholia
Brezski RJ, Monroe JG.; ''B-cell receptor.''; PubMed Europe PMC Scholia
Hennig A, Markwart R, Esparza-Franco MA, Ladds G, Rubio I.; ''Ras activation revisited: role of GEF and GAP systems.''; PubMed Europe PMC Scholia
Huang EJ, Reichardt LF.; ''Trk receptors: roles in neuronal signal transduction.''; PubMed Europe PMC Scholia
Parrella E, Longo VD.; ''Insulin/IGF-I and related signaling pathways regulate aging in nondividing cells: from yeast to the mammalian brain.''; PubMed Europe PMC Scholia
Akdis M, Burgler S, Crameri R, Eiwegger T, Fujita H, Gomez E, Klunker S, Meyer N, O'Mahony L, Palomares O, Rhyner C, Ouaked N, Schaffartzik A, Van De Veen W, Zeller S, Zimmermann M, Akdis CA.; ''Interleukins, from 1 to 37, and interferon-γ: receptors, functions, and roles in diseases.''; PubMed Europe PMC Scholia
Tessarz AS, Cerwenka A.; ''The TREM-1/DAP12 pathway.''; PubMed Europe PMC Scholia
Tsang M, Friesel R, Kudoh T, Dawid IB.; ''Identification of Sef, a novel modulator of FGF signalling.''; PubMed Europe PMC Scholia
Estep AL, Palmer C, McCormick F, Rauen KA.; ''Mutation analysis of BRAF, MEK1 and MEK2 in 15 ovarian cancer cell lines: implications for therapy.''; PubMed Europe PMC Scholia
Fürthauer M, Lin W, Ang SL, Thisse B, Thisse C.; ''Sef is a feedback-induced antagonist of Ras/MAPK-mediated FGF signalling.''; PubMed Europe PMC Scholia
Dougherty MK, Müller J, Ritt DA, Zhou M, Zhou XZ, Copeland TD, Conrads TP, Veenstra TD, Lu KP, Morrison DK.; ''Regulation of Raf-1 by direct feedback phosphorylation.''; PubMed Europe PMC Scholia
Kondoh K, Nishida E.; ''Regulation of MAP kinases by MAP kinase phosphatases.''; PubMed Europe PMC Scholia
Raabe T, Rapp UR.; ''Ras signaling: PP2A puts Ksr and Raf in the right place.''; PubMed Europe PMC Scholia
Riese DJ, van Raaij TM, Plowman GD, Andrews GC, Stern DF.; ''The cellular response to neuregulins is governed by complex interactions of the erbB receptor family.''; PubMed Europe PMC Scholia
Samatar AA, Poulikakos PI.; ''Targeting RAS-ERK signalling in cancer: promises and challenges.''; PubMed Europe PMC Scholia
Matallanas D, Birtwistle M, Romano D, Zebisch A, Rauch J, von Kriegsheim A, Kolch W.; ''Raf family kinases: old dogs have learned new tricks.''; PubMed Europe PMC Scholia
Roy M, Li Z, Sacks DB.; ''IQGAP1 is a scaffold for mitogen-activated protein kinase signaling.''; PubMed Europe PMC Scholia
Catalanotti F, Reyes G, Jesenberger V, Galabova-Kovacs G, de Matos Simoes R, Carugo O, Baccarini M.; ''A Mek1-Mek2 heterodimer determines the strength and duration of the Erk signal.''; PubMed Europe PMC Scholia
Geng F, Zhang J, Wu JL, Zou WJ, Liang ZP, Bi LL, Liu JH, Kong Y, Huang CQ, Li XW, Yang JM, Gao TM.; ''Neuregulin 1-ErbB4 signaling in the bed nucleus of the stria terminalis regulates anxiety-like behavior.''; PubMed Europe PMC Scholia
Sweeney C, Lai C, Riese DJ, Diamonti AJ, Cantley LC, Carraway KL.; ''Ligand discrimination in signaling through an ErbB4 receptor homodimer.''; PubMed Europe PMC Scholia
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Terai K, Matsuda M.; ''Ras binding opens c-Raf to expose the docking site for mitogen-activated protein kinase kinase.''; PubMed Europe PMC Scholia
Marks JL, Gong Y, Chitale D, Golas B, McLellan MD, Kasai Y, Ding L, Mardis ER, Wilson RK, Solit D, Levine R, Michel K, Thomas RK, Rusch VW, Ladanyi M, Pao W.; ''Novel MEK1 mutation identified by mutational analysis of epidermal growth factor receptor signaling pathway genes in lung adenocarcinoma.''; PubMed Europe PMC Scholia
Rodriguez-Viciana P, Warne PH, Vanhaesebroeck B, Waterfield MD, Downward J.; ''Activation of phosphoinositide 3-kinase by interaction with Ras and by point mutation.''; PubMed Europe PMC Scholia
Gentry LR, Martin TD, Reiner DJ, Der CJ.; ''Ral small GTPase signaling and oncogenesis: More than just 15minutes of fame.''; PubMed Europe PMC Scholia
Nakamura A, Arita T, Tsuchiya S, Donelan J, Chouitar J, Carideo E, Galvin K, Okaniwa M, Ishikawa T, Yoshida S.; ''Antitumor activity of the selective pan-RAF inhibitor TAK-632 in BRAF inhibitor-resistant melanoma.''; PubMed Europe PMC Scholia
Lito P, Saborowski A, Yue J, Solomon M, Joseph E, Gadal S, Saborowski M, Kastenhuber E, Fellmann C, Ohara K, Morikami K, Miura T, Lukacs C, Ishii N, Lowe S, Rosen N.; ''Disruption of CRAF-mediated MEK activation is required for effective MEK inhibition in KRAS mutant tumors.''; PubMed Europe PMC Scholia
Stowe IB, Mercado EL, Stowe TR, Bell EL, Oses-Prieto JA, Hernández H, Burlingame AL, McCormick F.; ''A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1.''; PubMed Europe PMC Scholia
Hu J, Stites EC, Yu H, Yu H, Germino EA, Meharena HS, Stork PJS, Kornev AP, Taylor SS, Shaw AS.; ''Allosteric activation of functionally asymmetric RAF kinase dimers.''; PubMed Europe PMC Scholia
Kainulainen V, Sundvall M, Määttä JA, Santiestevan E, Klagsbrun M, Elenius K.; ''A natural ErbB4 isoform that does not activate phosphoinositide 3-kinase mediates proliferation but not survival or chemotaxis.''; PubMed Europe PMC Scholia
Chaikuad A, Tacconi EM, Zimmer J, Liang Y, Gray NS, Tarsounas M, Knapp S.; ''A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics.''; PubMed Europe PMC Scholia
Cheng QC, Tikhomirov O, Zhou W, Carpenter G.; ''Ectodomain cleavage of ErbB-4: characterization of the cleavage site and m80 fragment.''; PubMed Europe PMC Scholia
Bourne HR, Sanders DA, McCormick F.; ''The GTPase superfamily: conserved structure and molecular mechanism.''; PubMed Europe PMC Scholia
Tohgo A, Choy EW, Gesty-Palmer D, Pierce KL, Laporte S, Oakley RH, Caron MG, Lefkowitz RJ, Luttrell LM.; ''The stability of the G protein-coupled receptor-beta-arrestin interaction determines the mechanism and functional consequence of ERK activation.''; PubMed Europe PMC Scholia
Coggeshall KM, McHugh JC, Altman A.; ''Predominant expression and activation-induced tyrosine phosphorylation of phospholipase C-gamma 2 in B lymphocytes.''; PubMed Europe PMC Scholia
Vigil D, Cherfils J, Rossman KL, Der CJ.; ''Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy?''; PubMed Europe PMC Scholia
Catling AD, Schaeffer HJ, Reuter CW, Reddy GR, Weber MJ.; ''A proline-rich sequence unique to MEK1 and MEK2 is required for raf binding and regulates MEK function.''; PubMed Europe PMC Scholia
Chitnis MM, Yuen JS, Protheroe AS, Pollak M, Macaulay VM.; ''The type 1 insulin-like growth factor receptor pathway.''; PubMed Europe PMC Scholia
Suire S, Hawkins P, Stephens L.; ''Activation of phosphoinositide 3-kinase gamma by Ras.''; PubMed Europe PMC Scholia
Chen C, Lewis RE, White MA.; ''IMP modulates KSR1-dependent multivalent complex formation to specify ERK1/2 pathway activation and response thresholds.''; PubMed Europe PMC Scholia
Bradshaw JM.; ''The Src, Syk, and Tec family kinases: distinct types of molecular switches.''; PubMed Europe PMC Scholia
Gripp KW, Aldinger KA, Bennett JT, Baker L, Tusi J, Powell-Hamilton N, Stabley D, Sol-Church K, Timms AE, Dobyns WB.; ''A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair.''; PubMed Europe PMC Scholia
Hu J, Yu H, Yu H, Kornev AP, Zhao J, Filbert EL, Taylor SS, Shaw AS.; ''Mutation that blocks ATP binding creates a pseudokinase stabilizing the scaffolding function of kinase suppressor of Ras, CRAF and BRAF.''; PubMed Europe PMC Scholia
Lavoie H, Therrien M.; ''Regulation of RAF protein kinases in ERK signalling.''; PubMed Europe PMC Scholia
Morris EJ, Jha S, Restaino CR, Dayananth P, Zhu H, Cooper A, Carr D, Deng Y, Jin W, Black S, Long B, Liu J, Dinunzio E, Windsor W, Zhang R, Zhao S, Angagaw MH, Pinheiro EM, Desai J, Xiao L, Shipps G, Hruza A, Wang J, Kelly J, Paliwal S, Gao X, Babu BS, Zhu L, Daublain P, Zhang L, Lutterbach BA, Pelletier MR, Philippar U, Siliphaivanh P, Witter D, Kirschmeier P, Bishop WR, Hicklin D, Gilliland DG, Jayaraman L, Zawel L, Fawell S, Samatar AA.; ''Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors.''; PubMed Europe PMC Scholia
Shin SY, Rath O, Choo SM, Fee F, McFerran B, Kolch W, Cho KH.; ''Positive- and negative-feedback regulations coordinate the dynamic behavior of the Ras-Raf-MEK-ERK signal transduction pathway.''; PubMed Europe PMC Scholia
Montagut C, Sharma SV, Shioda T, McDermott U, Ulman M, Ulkus LE, Dias-Santagata D, Stubbs H, Lee DY, Singh A, Drew L, Haber DA, Settleman J.; ''Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma.''; PubMed Europe PMC Scholia
Teis D, Wunderlich W, Huber LA.; ''Localization of the MP1-MAPK scaffold complex to endosomes is mediated by p14 and required for signal transduction.''; PubMed Europe PMC Scholia
Feng SM, Muraoka-Cook RS, Hunter D, Sandahl MA, Caskey LS, Miyazawa K, Atfi A, Earp HS.; ''The E3 ubiquitin ligase WWP1 selectively targets HER4 and its proteolytically derived signaling isoforms for degradation.''; PubMed Europe PMC Scholia
Cseh B, Doma E, Baccarini M.; ''"RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway.''; PubMed Europe PMC Scholia
Ohren JF, Chen H, Pavlovsky A, Whitehead C, Zhang E, Kuffa P, Yan C, McConnell P, Spessard C, Banotai C, Mueller WT, Delaney A, Omer C, Sebolt-Leopold J, Dudley DT, Leung IK, Flamme C, Warmus J, Kaufman M, Barrett S, Tecle H, Hasemann CA.; ''Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition.''; PubMed Europe PMC Scholia
Heldin CH, Westermark B.; ''Mechanism of action and in vivo role of platelet-derived growth factor.''; PubMed Europe PMC Scholia
Salzano M, Rusciano MR, Russo E, Bifulco M, Postiglione L, Vitale M.; ''Calcium/calmodulin-dependent protein kinase II (CaMKII) phosphorylates Raf-1 at serine 338 and mediates Ras-stimulated Raf-1 activation.''; PubMed Europe PMC Scholia
Boga SB, Deng Y, Zhu L, Nan Y, Cooper AB, Shipps GW, Doll R, Shih NY, Zhu H, Sun R, Wang T, Paliwal S, Tsui HC, Gao X, Yao X, Desai J, Wang J, Alhassan AB, Kelly J, Patel M, Muppalla K, Gudipati S, Zhang LK, Buevich A, Hesk D, Carr D, Dayananth P, Black S, Mei H, Cox K, Sherborne B, Hruza AW, Xiao L, Jin W, Long B, Liu G, Taylor SA, Kirschmeier P, Windsor WT, Bishop R, Samatar AA.; ''MK-8353: Discovery of an Orally Bioavailable Dual Mechanism ERK Inhibitor for Oncology.''; PubMed Europe PMC Scholia
Luo X, Feng L, Jiang X, Xiao F, Wang Z, Feng GS, Chen Y.; ''Characterization of the topology and functional domains of RKTG.''; PubMed Europe PMC Scholia
Prior IA, Lewis PD, Mattos C.; ''A comprehensive survey of Ras mutations in cancer.''; PubMed Europe PMC Scholia
Baldock D, Graham B, Akhlaq M, Graff P, Jones CE, Menear K.; ''Purification and characterization of human Syk produced using a baculovirus expression system.''; PubMed Europe PMC Scholia
Herbst RS.; ''Review of epidermal growth factor receptor biology.''; PubMed Europe PMC Scholia
Roskoski R.; ''MEK1/2 dual-specificity protein kinases: structure and regulation.''; PubMed Europe PMC Scholia
Brunet A, Pagès G, Pouysségur J.; ''Growth factor-stimulated MAP kinase induces rapid retrophosphorylation and inhibition of MAP kinase kinase (MEK1).''; PubMed Europe PMC Scholia
Crosier PS, Ricciardi ST, Hall LR, Vitas MR, Clark SC, Crosier KE.; ''Expression of isoforms of the human receptor tyrosine kinase c-kit in leukemic cell lines and acute myeloid leukemia.''; PubMed Europe PMC Scholia
Chen RH, Sarnecki C, Blenis J.; ''Nuclear localization and regulation of erk- and rsk-encoded protein kinases.''; PubMed Europe PMC Scholia
Muraoka-Cook RS, Caskey LS, Sandahl MA, Hunter DM, Husted C, Strunk KE, Sartor CI, Rearick WA, McCall W, Sgagias MK, Cowan KH, Earp HS.; ''Heregulin-dependent delay in mitotic progression requires HER4 and BRCA1.''; PubMed Europe PMC Scholia
Zeng F, Xu J, Harris RC.; ''Nedd4 mediates ErbB4 JM-a/CYT-1 ICD ubiquitination and degradation in MDCK II cells.''; PubMed Europe PMC Scholia
Lemmon MA, Schlessinger J.; ''Cell signaling by receptor tyrosine kinases.''; PubMed Europe PMC Scholia
Relou IA, Bax LA, van Rijn HJ, Akkerman JW.; ''Site-specific phosphorylation of platelet focal adhesion kinase by low-density lipoprotein.''; PubMed Europe PMC Scholia
Whittaker SR, Theurillat JP, Van Allen E, Wagle N, Hsiao J, Cowley GS, Schadendorf D, Root DE, Garraway LA.; ''A genome-scale RNA interference screen implicates NF1 loss in resistance to RAF inhibition.''; PubMed Europe PMC Scholia
Schulze WX, Deng L, Mann M.; ''Phosphotyrosine interactome of the ErbB-receptor kinase family.''; PubMed Europe PMC Scholia
Schlessinger J.; ''Ligand-induced, receptor-mediated dimerization and activation of EGF receptor.''; PubMed Europe PMC Scholia
Matsubayashi Y, Fukuda M, Nishida E.; ''Evidence for existence of a nuclear pore complex-mediated, cytosol-independent pathway of nuclear translocation of ERK MAP kinase in permeabilized cells.''; PubMed Europe PMC Scholia
Blank U, Rivera J.; ''The ins and outs of IgE-dependent mast-cell exocytosis.''; PubMed Europe PMC Scholia
Cherfils J, Zeghouf M.; ''Regulation of small GTPases by GEFs, GAPs, and GDIs.''; PubMed Europe PMC Scholia
McGillicuddy LT, Fromm JA, Hollstein PE, Kubek S, Beroukhim R, De Raedt T, Johnson BW, Williams SM, Nghiemphu P, Liau LM, Cloughesy TF, Mischel PS, Parret A, Seiler J, Moldenhauer G, Scheffzek K, Stemmer-Rachamimov AO, Sawyers CL, Brennan C, Messiaen L, Mellinghoff IK, Cichowski K.; ''Proteasomal and genetic inactivation of the NF1 tumor suppressor in gliomagenesis.''; PubMed Europe PMC Scholia
Chadee DN, Kyriakis JM.; ''A novel role for mixed lineage kinase 3 (MLK3) in B-Raf activation and cell proliferation.''; PubMed Europe PMC Scholia
Paatero I, Jokilammi A, Heikkinen PT, Iljin K, Kallioniemi OP, Jones FE, Jaakkola PM, Elenius K.; ''Interaction with ErbB4 promotes hypoxia-inducible factor-1α signaling.''; PubMed Europe PMC Scholia
King PD, Lubeck BA, Lapinski PE.; ''Nonredundant functions for Ras GTPase-activating proteins in tissue homeostasis.''; PubMed Europe PMC Scholia
Cantwell-Dorris ER, O'Leary JJ, Sheils OM.; ''BRAFV600E: implications for carcinogenesis and molecular therapy.''; PubMed Europe PMC Scholia

History

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Revision	Action	Time	User	Comment
114761	view	16:25, 25 January 2021	ReactomeTeam	Reactome version 75
113205	view	11:27, 2 November 2020	ReactomeTeam	Reactome version 74
112429	view	15:37, 9 October 2020	ReactomeTeam	Reactome version 73
101333	view	11:22, 1 November 2018	ReactomeTeam	reactome version 66
100871	view	20:55, 31 October 2018	ReactomeTeam	reactome version 65
100412	view	19:28, 31 October 2018	ReactomeTeam	reactome version 64
99961	view	16:13, 31 October 2018	ReactomeTeam	reactome version 63
99516	view	14:46, 31 October 2018	ReactomeTeam	reactome version 62 (2nd attempt)
99158	view	12:41, 31 October 2018	ReactomeTeam	reactome version 62
93933	view	13:46, 16 August 2017	ReactomeTeam	reactome version 61
93520	view	11:25, 9 August 2017	ReactomeTeam	reactome version 61
88127	view	10:15, 26 July 2016	Ryanmiller	Ontology Term : 'kinase mediated signaling pathway' added !
88126	view	10:15, 26 July 2016	Ryanmiller	Ontology Term : 'signaling pathway' added !
86618	view	09:22, 11 July 2016	ReactomeTeam	reactome version 56
83142	view	10:09, 18 November 2015	ReactomeTeam	Version54
81486	view	13:01, 21 August 2015	ReactomeTeam	Version53
76963	view	08:24, 17 July 2014	ReactomeTeam	Fixed remaining interactions
76668	view	12:03, 16 July 2014	ReactomeTeam	Fixed remaining interactions
75998	view	10:05, 11 June 2014	ReactomeTeam	Re-fixing comment source
75701	view	11:04, 10 June 2014	ReactomeTeam	Reactome 48 Update
75057	view	13:56, 8 May 2014	Anwesha	Fixing comment source for displaying WikiPathways description
74701	view	08:46, 30 April 2014	ReactomeTeam	New pathway

External references

DataNodes

View all...

Name	Type	Database reference
ADP	Metabolite	CHEBI:16761 (ChEBI)
ATP	Metabolite	CHEBI:15422 (ChEBI)
Activated RAF1 complex:MEK1	Complex	REACT_4256 (Reactome)
Activated RAF1 complex:MEK2	Complex	REACT_4223 (Reactome)
Activated RAF1 complex:MEK	Complex	REACT_3953 (Reactome)
Activated RAF1 complex	Complex	REACT_4906 (Reactome)
GTP [cytosol]	Metabolite	CHEBI:15996 (ChEBI)
HRAS(1-186) [plasma membrane]	Protein	P01112 (Uniprot-TrEMBL)
HRAS:GTP	Complex	REACT_24217 (Reactome)
KRAS(1-186) [plasma membrane]	Protein	P01116 (Uniprot-TrEMBL)
MAP2K1 [cytosol]	Protein	Q02750 (Uniprot-TrEMBL)
MAP2K2 [cytosol]	Protein	P36507 (Uniprot-TrEMBL)
MAPK1 [cytosol]	Protein	P28482 (Uniprot-TrEMBL)
MAPK1	Protein	P28482 (Uniprot-TrEMBL)
MAPK3 [cytosol]	Protein	P27361 (Uniprot-TrEMBL)
MAPK3	Protein	P27361 (Uniprot-TrEMBL)
MEK1:ERK-1	Complex	REACT_5539 (Reactome)
MEK1		REACT_2607 (Reactome)
MEK2:ERK-2	Complex	REACT_5435 (Reactome)
MEK	Protein	REACT_2275 (Reactome)
NRAS [plasma membrane]	Protein	P01111 (Uniprot-TrEMBL)
RAS:RAF:14-3-3	Complex	REACT_3642 (Reactome)
RAS:RAF	Complex	REACT_3036 (Reactome)
Ras:GTP:p-Raf1(S259,S621)	Complex	REACT_24177 (Reactome)
YWHAB(1-246) [cytosol]	Protein	P31946 (Uniprot-TrEMBL)
YWHAB(1-246)	Protein	P31946 (Uniprot-TrEMBL)
p-MEK1	Protein	REACT_3339 (Reactome)
p-Raf1(S259,S621):14-3-3 protein beta/alpha	Complex	REACT_4612 (Reactome)
p-S,T-MAP2K2 [cytosol]	Protein	P36507 (Uniprot-TrEMBL)
p-S,T-MAP2K2	Protein	P36507 (Uniprot-TrEMBL)
p-S218,S222-MAP2K1 [cytosol]	Protein	Q02750 (Uniprot-TrEMBL)
p-S218,S222-MAP2K1	Protein	Q02750 (Uniprot-TrEMBL)
p-S259,S621-RAF1 [cytosol]	Protein	P04049 (Uniprot-TrEMBL)
p-S259,S621-RAF1	Protein	P04049 (Uniprot-TrEMBL)
p-S259,Y340,Y341,S621-RAF1 [plasma membrane]	Protein	P04049 (Uniprot-TrEMBL)
p-T161-CDK1	Protein	P06493 (Uniprot-TrEMBL)
p-T185,Y187-MAPK1 [cytosol]	Protein	P28482 (Uniprot-TrEMBL)
p-T185,Y187-MAPK1 [nucleoplasm]	Protein	P28482 (Uniprot-TrEMBL)
p-T185,Y187-MAPK1	Protein	P28482 (Uniprot-TrEMBL)
p-T202,Y204-MAPK3 [cytosol]	Protein	P27361 (Uniprot-TrEMBL)
p-T202,Y204-MAPK3 [nucleoplasm]	Protein	P27361 (Uniprot-TrEMBL)
p-T202,Y204-MAPK3	Protein	P27361 (Uniprot-TrEMBL)
p21 RAS:GTP	Complex	REACT_4782 (Reactome)
phospho-ERK-1 dimer	Complex	REACT_3152 (Reactome)
phospho-ERK-1 dimer	Complex	REACT_3932 (Reactome)
phospho-ERK-1:MEK1	Complex	REACT_2796 (Reactome)
phospho-ERK-2 dimer	Complex	REACT_3688 (Reactome)
phospho-ERK-2 dimer	Complex	REACT_5046 (Reactome)
phospho-ERK-2:MEK2	Complex	REACT_3199 (Reactome)
unidentified protein tyrosine kinase		REACT_4938 (Reactome)

Annotated Interactions

View all...

Source	Target	Type	Database reference	Comment
	ADP	Arrow	REACT_136 (Reactome)
	ADP	Arrow	REACT_1727 (Reactome)
	ADP	Arrow	REACT_1836 (Reactome)
	ADP	Arrow	REACT_2247 (Reactome)
	ADP	Arrow	REACT_525 (Reactome)
	ADP	Arrow	REACT_545 (Reactome)
ATP			REACT_136 (Reactome)
ATP			REACT_1727 (Reactome)
ATP			REACT_1836 (Reactome)
ATP			REACT_2247 (Reactome)
ATP			REACT_525 (Reactome)
ATP			REACT_545 (Reactome)
Activated RAF1 complex:MEK1			REACT_545 (Reactome)
Activated RAF1 complex:MEK2			REACT_1727 (Reactome)
	Activated RAF1 complex:MEK	Arrow	REACT_143 (Reactome)
Activated RAF1 complex:MEK		mim-catalysis	REACT_1727 (Reactome)
Activated RAF1 complex:MEK		mim-catalysis	REACT_545 (Reactome)
	Activated RAF1 complex	Arrow	REACT_1727 (Reactome)
	Activated RAF1 complex	Arrow	REACT_525 (Reactome)
	Activated RAF1 complex	Arrow	REACT_545 (Reactome)
Activated RAF1 complex			REACT_143 (Reactome)
HRAS:GTP			REACT_23877 (Reactome)
MAPK1			REACT_495 (Reactome)
MAPK3			REACT_1780 (Reactome)
	MEK1:ERK-1	Arrow	REACT_1780 (Reactome)
MEK1:ERK-1			REACT_136 (Reactome)
MEK1:ERK-1		mim-catalysis	REACT_136 (Reactome)
MEK1			REACT_1836 (Reactome)
	MEK2:ERK-2	Arrow	REACT_495 (Reactome)
MEK2:ERK-2			REACT_2247 (Reactome)
MEK2:ERK-2		mim-catalysis	REACT_2247 (Reactome)
MEK			REACT_143 (Reactome)
	RAS:RAF:14-3-3	Arrow	REACT_996 (Reactome)
RAS:RAF:14-3-3			REACT_525 (Reactome)
	RAS:RAF	Arrow	REACT_359 (Reactome)
RAS:RAF			REACT_996 (Reactome)
			REACT_1019 (Reactome)	MEK2 dissociates from phospho-ERK2, allowing phospho-ERK2 to dimerise with another phospho-ERK2.
			REACT_1289 (Reactome)	Two phospho-ERK1 molecules dimerise and enter the nucleus, where they may phosphorylate downstream targets.
			REACT_136 (Reactome)	MEK1 phosphorylates the critical Tyrosine and Threonine on ERK1, converting two ATP to ADP. Phosphorylation of ERK-1 activates its kinase activity.
			REACT_143 (Reactome)	MEK-1/2 have a proline rich domain (P) and critical Serine residues (MEK-1 S218/222, MEK-2 unknown, S) upon which the molecules may be phosphorylated. MEK1/2 are found in the cytoplasm of unstimulated cells. MEK-1/2 bind to active Raf-1 via the proline-rich domain. Active Raf-1 is able to phosphorylate target Serine and Threonine residues in the presence of ATP.
			REACT_1727 (Reactome)	Active Raf-1 phosphorylates MEK-1/2 on Serine residues, converting ATP to ADP. The MEK-1/2 kinase is now active.
			REACT_1740 (Reactome)	MEK1 dissociates from phospho-ERK1, allowing phospho-ERK1 to dimerise with another phospho-ERK1.
			REACT_1780 (Reactome)	In the cytoplasm activated MEK1 (Serine phosphorylated) may encounter monomeric, inactive ERK1. ERK1 in its inactive form is not phosphorylated on a critical Threonine (T) and a critical Tyrosine (Y).
			REACT_1836 (Reactome)	At the beginning of this reaction, 2 molecules of 'ATP', and 1 molecule of 'MEK1' are present. At the end of this reaction, 1 molecule of 'phospho_MEK1', and 2 molecules of 'ADP' are present. This reaction takes place in the 'cytosol' and is mediated by the 'protein serine/threonine kinase activity' of 'phospho-Cdc2 (Thr 161)'.
			REACT_1866 (Reactome)	Phospho-ERK-1 dimer is translocated from cytosol to nucleoplasm.
			REACT_2158 (Reactome)	Inactive Raf-1 is associated in the cytoplasm with 14-3-3. 14-3-3 binds to Raf-1 via the Ser259 phosphorylation site (S1). This interaction stabilises the inactive conformation of Raf-1 in which the Ras-binding Cysteine-rich domain (CRD) is obscured. The Raf-1 molecule contains an additional p21ras-binding domain (RBD), a second serine phosphorylation site at S621 (S2) and two tyrosine phosphorylation sites (at 340, Y1 and 341, Y2).
			REACT_2196 (Reactome)	Two phospho-ERK2 molecules dimerise and enter the nucleus, where they may phosphorylate downstream targets.
			REACT_2247 (Reactome)	MEK2 phosphorylates the critical Tyrosine and Threonine on ERK2, converting two ATP to ADP. Phosphorylation of ERK-2 activates its kinase activity.
			REACT_23877 (Reactome)	A key event for Ras transformation involves the direct physical association between Ras and the Raf-1 kinase. This interaction promotes both Raf translocation to the plasma membrane and activation of Raf kinase activity.
			REACT_359 (Reactome)	Activated p21ras (the GTP-bound form) is associated with the plasma membrane. Inactive Raf-1 is associated in the cytoplasm with 14-3-3. 14-3-3 binds to Raf-1 via the Ser259 phosphorylation site (S1). This interaction stabilises the inactive conformation of Raf-1 in which the Ras-binding Cysteine-rich domain (CRD) is obscured. The Raf-1 molecule contains an additional p21ras-binding domain (RBD), a second serine phosphorylation site at S621 (S2) and two tyrosine phosphorylation sites (at 340, Y1 and 341, Y2). Raf-1 binds activated p21ras via the RBD. This displaces 14-3-3 from Ser259 and unmasks the CRD.
			REACT_487 (Reactome)	Phospho-ERK-2 dimer is translocated from cytosol to nucleoplasm.
			REACT_495 (Reactome)	In the cytoplasm activated MEK2 (Serine phosphorylated) may encounter monomeric, inactive ERK2. ERK2 in its inactive form is not phosphorylated on a critical Threonine (T183) and a critical Tyrosine (Y185).
			REACT_525 (Reactome)	An unidentified protein tyrosine kinase located in the plasma membrane phosphorylates tyrosine residues at 340 and 341 (Y1, Y2 in diagram) of Raf-1. This serves to further stabilise the active 'open' Raf-1 conformation. While the kinase has not been definitively identified, Src is a plausible candidate: coexpression of Raf-1 and Src in Sf9 cells resulted in phosphorylation of Y340/Y341 and enzymatic activationof Raf-1; Raf-1 interacts with Src and co-immunoprecipitates with Src/Fyn in NIH-3T3 cells.
			REACT_545 (Reactome)	Active Raf-1 phosphorylates MEK-1/2 on Serine residues, converting ATP to ADP. The MEK-1/2 kinase is now active.
			REACT_996 (Reactome)	14-3-3 has been displaced from Ser259. 14-3-3 may now bind its higher affinity Ser621 (S2) site. This stabilises an 'open' Raf-1 conformation that is catalytically active, and bound to p21ras via both p21ras-binding domains, CRD and RBD.
	Ras:GTP:p-Raf1(S259,S621)	Arrow	REACT_23877 (Reactome)
	YWHAB(1-246)	Arrow	REACT_359 (Reactome)
YWHAB(1-246)			REACT_2158 (Reactome)
YWHAB(1-246)			REACT_996 (Reactome)
	p-MEK1	Arrow	REACT_1836 (Reactome)
p-MEK1		TBar	REACT_136 (Reactome)
	p-Raf1(S259,S621):14-3-3 protein beta/alpha	Arrow	REACT_2158 (Reactome)
p-Raf1(S259,S621):14-3-3 protein beta/alpha			REACT_359 (Reactome)
	p-S,T-MAP2K2	Arrow	REACT_1019 (Reactome)
	p-S,T-MAP2K2	Arrow	REACT_1727 (Reactome)
p-S,T-MAP2K2			REACT_495 (Reactome)
	p-S218,S222-MAP2K1	Arrow	REACT_1740 (Reactome)
	p-S218,S222-MAP2K1	Arrow	REACT_545 (Reactome)
p-S218,S222-MAP2K1			REACT_1780 (Reactome)
p-S259,S621-RAF1			REACT_2158 (Reactome)
p-S259,S621-RAF1			REACT_23877 (Reactome)
p-T161-CDK1		mim-catalysis	REACT_1836 (Reactome)
	p-T185,Y187-MAPK1	Arrow	REACT_1019 (Reactome)
p-T185,Y187-MAPK1			REACT_2196 (Reactome)
	p-T202,Y204-MAPK3	Arrow	REACT_1740 (Reactome)
p-T202,Y204-MAPK3			REACT_1289 (Reactome)
p21 RAS:GTP			REACT_359 (Reactome)
	phospho-ERK-1 dimer	Arrow	REACT_1289 (Reactome)
	phospho-ERK-1 dimer	Arrow	REACT_1866 (Reactome)
phospho-ERK-1 dimer			REACT_1866 (Reactome)
	phospho-ERK-1:MEK1	Arrow	REACT_136 (Reactome)
phospho-ERK-1:MEK1			REACT_1740 (Reactome)
	phospho-ERK-2 dimer	Arrow	REACT_2196 (Reactome)
	phospho-ERK-2 dimer	Arrow	REACT_487 (Reactome)
phospho-ERK-2 dimer			REACT_487 (Reactome)
	phospho-ERK-2:MEK2	Arrow	REACT_2247 (Reactome)
phospho-ERK-2:MEK2			REACT_1019 (Reactome)
unidentified protein tyrosine kinase		mim-catalysis	REACT_525 (Reactome)

RAF/MAP kinase cascade (Homo sapiens)

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