BioPAX pathway converted from "Negative regulation of MAPK pathway" in the Reactome database.Negative regulation of MAPK pathwayNegative regulation of MAPK pathwayThis event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>PAQR3 binds inactive RAFsPAQR3 binds inactive RAFsThis event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>Reactome DB_ID: 103694231Golgi membraneGO0000139UniProt:B7ZUP2Reactomehttp://www.reactome.orgXenopus tropicalisNCBI Taxonomy8364UniProtB7ZUP2Chain Coordinates1EQUAL311EQUALConverted from EntitySet in ReactomeReactome DB_ID: 103691431cytosolGO0005829inactive RAFs [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityphospho-p-S259,S621-RAF1 [cytosol]phospho-p-S365,S445,S729 BRAF [cytosol]UniProtF6RZI1UniProtF6V946Reactome DB_ID: 103694251PAQR3:inactive RAFs [Golgi membrane]PAQR3:inactive RAFsReactome DB_ID: 1036942311EQUAL311EQUALConverted from EntitySet in ReactomeReactome DB_ID: 103691431Reactome Database ID Release 7010369425Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10369425ReactomeR-XTR-56741391Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-5674139.1Reactome Database ID Release 7010369427Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10369427ReactomeR-XTR-56741401Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-5674140.1PAQR3, also known as RKTG (Raf kinase trapping to Golgi) is a multi-pass transmembrane protein that binds to RAF1 and BRAF and sequesters them in the Golgi. This inhibits the interaction of RAF with activated RAS and the plasma membrane and inhibits RAF signaling (Feng et al, 2007; Fan et al, 2008; Luo et al, 2008).18515281Pubmed2008RKTG sequesters B-Raf to the Golgi apparatus and inhibits the proliferation and tumorigenicity of human malignant melanoma cellsFan, FengjuanFeng, LinHe, JingWang, XiaoJiang, XiaomengZhang, YixuanWang, ZhenzhenChen, YanCarcinogenesis 29:1157-6318547165Pubmed2008Characterization of the topology and functional domains of RKTGLuo, XiaolinFeng, LinJiang, XiaomengXiao, FeiWang, ZhenzhenFeng, Gen-ShengChen, YanBiochem. J. 414:399-40617724343Pubmed2007Spatial regulation of Raf kinase signaling by RKTGFeng, LinXie, XiaoduoDing, QiurongLuo, XiaolinHe, JingFan, FengjuanLiu, WeizhongWang, ZhenzhenChen, YanProc. Natl. Acad. Sci. U.S.A. 104:14348-53inferred by electronic annotationIEAGOIEANegative feedback regulation of MAPK pathwayNegative feedback regulation of MAPK pathwayThis event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>2.7.11Activated MAPK phosphorylates RAF1Activated MAPK phosphorylates RAF1This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>Reactome DB_ID: 103692991plasma membraneGO0005886UniProt:F6RZI1O-phospho-L-serine at 621 (in Homo sapiens)621EQUALO-phospho-L-serine [MOD:00046]O4'-phospho-L-tyrosine at 341 (in Homo sapiens)341EQUALO4'-phospho-L-tyrosine [MOD:00048]O-phospho-L-serine at 338 (in Homo sapiens)338EQUALO-phospho-L-threonine at 491 (in Homo sapiens)491EQUALO-phospho-L-threonine [MOD:00047]O-phospho-L-serine at 494 (in Homo sapiens)494EQUAL1EQUAL648EQUALReactome DB_ID: 1135926ATP(4-) [ChEBI:30616]ATP(4-)Adenosine 5'-triphosphateatpATPChEBI30616Reactome DB_ID: 103694571O-phospho-L-serine at 621 (in Homo sapiens)621EQUALO4'-phospho-L-tyrosine at 341 (in Homo sapiens)341EQUALO-phospho-L-serine at 338 (in Homo sapiens)338EQUALO-phospho-L-threonine at 491 (in Homo sapiens)491EQUALO-phospho-L-serine at 494 (in Homo sapiens)494EQUALO-phospho-L-serine at 29 (in Homo sapiens)29EQUALO-phospho-L-serine at 43 (in Homo sapiens)43EQUALO-phospho-L-serine at 259 (in Homo sapiens)259EQUALO-phospho-L-serine at 296 (in Homo sapiens)296EQUALO-phospho-L-serine at 301 (in Homo sapiens)301EQUALO-phospho-L-serine at 642 (in Homo sapiens)642EQUAL1EQUAL648EQUALReactome DB_ID: 293706ADP(3-) [ChEBI:456216]ADP(3-)ADP trianion5&apos;-O-[(phosphonatooxy)phosphinato]adenosineADPChEBI456216PHYSIOL-LEFT-TO-RIGHTACTIVATIONConverted from EntitySet in ReactomeReactome DB_ID: 10369444p-T,Y MAPK monomers and dimers [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityphospho-p-T202,Y204-MAPK3 [cytosol]phospho-p-T185,Y187-MAPK1 [cytosol]UniProtF7EH19GO0004674GO molecular functionReactome Database ID Release 7010369458Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10369458Reactome Database ID Release 7010369460Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10369460ReactomeR-XTR-56751941Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-5675194.1RAF1 is phosphorylated by activated MAPK at 6 serine residues (S29, S43, S289, S296, S301 and S642). MAPK-dependent hyperphosphorylation of RAF1 abrogates the ability of activated RAF1 to interact with RAS and is coincident with inactivation of RAF1. RAF1 proteins containing mutation of these phosphorylation sites persist at the plasma membrane, show sustained S338 phosphorylation and persistent activation relative to WT RAF1 protein. In wild type cells, PP2A and the prolyl-isomerase PIN1 contribute to the dephosphorylation of hyperphosphorylated RAF1, allowing subsequent cycles of activation to occur (Dougherty et al, 2005; reviewed in Roskoski, 2010)15664191Pubmed2005Regulation of Raf-1 by direct feedback phosphorylationDougherty, Michele KMüller, JürgenRitt, Daniel AZhou, MingZhou, Xiao ZhenCopeland, Terry DConrads, Thomas PVeenstra, TDLu, Kun PingMorrison, Deborah KMol. Cell 17:215-2420674547Pubmed2010RAF protein-serine/threonine kinases: structure and regulationRoskoski, Robert JrBiochem. Biophys. Res. Commun. 399:313-7inferred by electronic annotationIEAGOIEA2.7.11Activated MAPKs phosphorylate BRAFActivated MAPKs phosphorylate BRAFThis event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>Reactome DB_ID: 103693011UniProt:F6V946O-phospho-L-serine at 445 (in Homo sapiens)445EQUALO-phospho-L-serine at 729 (in Homo sapiens)729EQUALO-phospho-L-threonine at 599 (in Homo sapiens)599EQUALO-phospho-L-serine at 602 (in Homo sapiens)602EQUAL2EQUAL766EQUALReactome DB_ID: 1135924Reactome DB_ID: 103694661O-phospho-L-serine at 445 (in Homo sapiens)445EQUALO-phospho-L-serine at 729 (in Homo sapiens)729EQUALO-phospho-L-threonine at 599 (in Homo sapiens)599EQUALO-phospho-L-serine at 602 (in Homo sapiens)602EQUALO-phospho-L-serine at 151 (in Homo sapiens)151EQUALO-phospho-L-serine at 750 (in Homo sapiens)750EQUALO-phospho-L-serine at 753 (in Homo sapiens)753EQUALO-phospho-L-threonine at 401 (in Homo sapiens)401EQUAL2EQUAL766EQUALReactome DB_ID: 293704PHYSIOL-LEFT-TO-RIGHTACTIVATIONConverted from EntitySet in ReactomeReactome DB_ID: 10369444Reactome Database ID Release 7010369468Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10369468ReactomeR-XTR-56751981Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-5675198.1BRAF is subject to MAPK-dependent phosphorylation that limits its activity. Phosphorylation of S151 inhibits binding of BRAF to activated RAS, while phosphorylation of T401, S750 and S753 abrogates heterodimerization with RAF1 (Ritt et al, 2010; Rushworth et al, 2006; Brummer et al, 2003).14654779Pubmed2003Identification of novel ERK-mediated feedback phosphorylation sites at the C-terminus of B-RafBrummer, TilmanNaegele, HeikeReth, MichaelMisawa, YukikoOncogene 22:8823-3419933846Pubmed2010Impact of feedback phosphorylation and Raf heterodimerization on normal and mutant B-Raf signalingRitt, Daniel AMonson, Daniel MSpecht, Suzanne IMorrison, Deborah KMol. Cell. Biol. 30:806-1916508002Pubmed2006Regulation and role of Raf-1/B-Raf heterodimerizationRushworth, Linda KHindley, Alison DO'Neill, EricKolch, WalterMol. Cell. Biol. 26:2262-72inferred by electronic annotationIEAGOIEAReactome Database ID Release 7010400144Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10400144ReactomeR-XTR-56744991Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-5674499.1MAPK pathway activation is limited by a number of negative feedback loops established by MAPK-dependent phosphorylations. Known substrates of activated MAPK proteins that lie upstream in the RAF/MAPK pathway include SOS, RAF1, BRAF, and MAP2K1 (Buday et al, 1995; Dong et al, 1996; Dougherty et al, 2005; Sturm et al, 2010; Fritsche-Guenther et al, 2011; Rushworth et al, 2006; Brummer et al, 2003; Ritt et al, 2010; Catalanotti et al, 2009)8626428Pubmed1996SOS phosphorylation and disassociation of the Grb2-SOS complex by the ERK and JNK signaling pathwaysDong Chen, D CWaters, Steven BHolt, Kathleen HPessin, JEJ. Biol. Chem. 271:6328-3221613978Pubmed2011Strong negative feedback from Erk to Raf confers robustness to MAPK signallingFritsche-Guenther, RaphaelaWitzel, FranziskaSieber, AnjaHerr, RicardaSchmidt, NadineBraun, SandraBrummer, TilmanSers, ChristineBlüthgen, NilsMol. Syst. Biol. 7:48921177493Pubmed2010The mammalian MAPK/ERK pathway exhibits properties of a negative feedback amplifierSturm, Oliver EOrton, RichardGrindlay, JoanBirtwistle, MarcVyshemirsky, VladislavGilbert, DavidCalder, MuffyPitt, AndrewKholodenko, BorisKolch, WalterSci Signal 3:ra907478553Pubmed1995Downregulation of the Ras activation pathway by MAP kinase phosphorylation of SosBuday, LWarne, P HDownward, JOncogene 11:1327-3119219045Pubmed2009A Mek1-Mek2 heterodimer determines the strength and duration of the Erk signalCatalanotti, FedericaReyes, GloriaJesenberger, VeronikaGalabova-Kovacs, Gerganade Matos Simoes, RicardoCarugo, OlivieroBaccarini, ManuelaNat. Struct. Mol. Biol. 16:294-303inferred by electronic annotationIEAGOIEAPEBP1 binds activated RAF1PEBP1 binds activated RAF1This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>Reactome DB_ID: 103693481UniProt:F6Y4G1UniProtF6Y4G12EQUAL187EQUALReactome DB_ID: 103693441p21RAS:GTP:activated RAF1 homo/heterodimer [plasma membrane]p21RAS:GTP:activated RAF1 homo/heterodimerReactome DB_ID: 103692991O-phospho-L-serine at 621 (in Homo sapiens)621EQUALO4'-phospho-L-tyrosine at 341 (in Homo sapiens)341EQUALO-phospho-L-serine at 338 (in Homo sapiens)338EQUALO-phospho-L-threonine at 491 (in Homo sapiens)491EQUALO-phospho-L-serine at 494 (in Homo sapiens)494EQUAL1EQUAL648EQUALReactome DB_ID: 103068771p21 RAS:GTP [plasma membrane]p21 RAS:GTPReactome DB_ID: 294381GTP [ChEBI:15996]GTPGuanosine 5'-triphosphateChEBI15996Converted from EntitySet in ReactomeReactome DB_ID: 103068751mature p21 RAS [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityS-Farn-Me PalmS NRAS [plasma membrane]S-Farn-Me-2xPalmS HRAS [plasma membrane]UniProtF6WDS0UniProtQ28EW2Reactome Database ID Release 7010306877Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10306877ReactomeR-XTR-1097831Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-109783.1Converted from EntitySet in ReactomeReactome DB_ID: 103691241'activator' RAFs [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityphospho-p-S445,S729-BRAF [cytosol]Reactome DB_ID: 102989991YWHAB dimer [cytosol]YWHAB dimerReactome DB_ID: 102989972UniProt:Q5XGC8UniProtQ5XGC81EQUAL246EQUALReactome Database ID Release 7010298999Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10298999ReactomeR-XTR-20286451Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-2028645.1Reactome Database ID Release 7010369344Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10369344ReactomeR-XTR-56754141Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-5675414.1Reactome DB_ID: 103693501p21 RAS:GTP:activated RAF1 homo/heterodimer:PEBP1 [plasma membrane]p21 RAS:GTP:activated RAF1 homo/heterodimer:PEBP1Reactome DB_ID: 1036934812EQUAL187EQUALReactome DB_ID: 103693441Reactome Database ID Release 7010369350Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10369350ReactomeR-XTR-56754131Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-5675413.1Reactome Database ID Release 7010369510Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10369510ReactomeR-XTR-56754171Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-5675417.1PEBP1, also known as RKIP (Raf kinase inhibitor protein), is a negative regulator of RAF1 that binds to the phosphorylated NtA region and prevents activation of MAP2K substrates (Yeung et al, 1999; Yeung et al, 2000; Rath et al, 2008; Park et al, 2006; reviewed in Lorenz et al, 2014). Relief of this PEBP1 repression of RAF1 activity is stimulated by phosphorylation of PEBP1, which promotes it dissociation from RAF1. Candidate kinases for phosphorylation of PEBP1 include PKC and the MAPKs themselves, which would establish a positive feedback loop stimulating MAPK pathway activity (Corbit et al, 2003; Cho et al, 2003; Shin et al, 2009).10757792Pubmed2000Mechanism of suppression of the Raf/MEK/extracellular signal-regulated kinase pathway by the raf kinase inhibitor proteinYeung, KamJanosch, PetraMcFerran, BrianRose, David WMischak, HSedivy, John MKolch, WalterMol. Cell. Biol. 20:3079-8517097642Pubmed2006Regulation of RKIP binding to the N-region of the Raf-1 kinasePark, SungdaeRath, OliverBeach, SandyXiang, XiaoqinKelly, Sharon MLuo, ZhijunKolch, WalterYeung, Kam CFEBS Lett. 580:6405-1210490027Pubmed1999Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIPYeung, KSeitz, TLi, SJanosch, PMcFerran, BKaiser, CFee, FKatsanakis, KDRose, DWMischak, HSedivy, JMKolch, WNature 401:173-719158341Pubmed2009Positive- and negative-feedback regulations coordinate the dynamic behavior of the Ras-Raf-MEK-ERK signal transduction pathwayShin, Sung-YoungRath, OliverChoo, Sang-MokFee, FrancesMcFerran, BrianKolch, WalterCho, Kwang-HyunJ. Cell. Sci. 122:425-3525597358Pubmed2014RKIP: a governor of intracellular signalingLorenz, KristinaSchmid, EvelynDeiss, KatharinaCrit Rev Oncog 19:489-9618294816Pubmed2008The RKIP (Raf-1 Kinase Inhibitor Protein) conserved pocket binds to the phosphorylated N-region of Raf-1 and inhibits the Raf-1-mediated activated phosphorylation of MEKRath, OliverPark, SungdaeTang, Hui-huiBanfield, Mark JBrady, R LeoLee, Yie ChiaDignam, John DSedivy, John MKolch, WalterYeung, Kam CCell. Signal. 20:935-41inferred by electronic annotationIEAGOIEAPP5 dephosphorylates RAF1 S338PP5 dephosphorylates RAF1 S338This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>Reactome DB_ID: 293561water [ChEBI:15377]waterChEBI15377Reactome DB_ID: 103693441Reactome DB_ID: 293721phosphate(3-) [ChEBI:18367]phosphate(3-)ChEBI18367Reactome DB_ID: 103695141p21RAS:GTP:dephosphorylated RAF1 homo/heterodimer [plasma membrane]p21RAS:GTP:dephosphorylated RAF1 homo/heterodimerReactome DB_ID: 103068771Reactome DB_ID: 103695121O-phospho-L-serine at 621 (in Homo sapiens)621EQUALO4'-phospho-L-tyrosine at 341 (in Homo sapiens)341EQUALO-phospho-L-threonine at 491 (in Homo sapiens)491EQUALO-phospho-L-serine at 494 (in Homo sapiens)494EQUAL1EQUAL648EQUALConverted from EntitySet in ReactomeReactome DB_ID: 103691241Reactome DB_ID: 102989991Reactome Database ID Release 7010369514Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10369514ReactomeR-XTR-56754301Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-5675430.1PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 10369525UniProt:F6UEJ5UniProtF6UEJ52EQUAL499EQUALGO0004722GO molecular functionReactome Database ID Release 7010369526Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10369526Reactome Database ID Release 7010369528Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10369528ReactomeR-XTR-56754331Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-5675433.1PPP5C dephosphorylates S338 in the NtA region of RAF1, which reduces the catalytic activity of RAF1 towards MAP2K proteins (von Kriegsheim et al, 2006; reviewed in Matallanas et al, 2011).16892053Pubmed2006Regulation of the Raf-MEK-ERK pathway by protein phosphatase 5von Kriegsheim, AlexPitt, AndrewGrindlay, G JoanKolch, WalterDhillon, Amardeep SNat. Cell Biol. 8:1011-621779496Pubmed2011Raf family kinases: old dogs have learned new tricksMatallanas, DavidBirtwistle, MarcRomano, DavidZebisch, ArminRauch, Jensvon Kriegsheim, AlexanderKolch, WalterGenes Cancer 2:232-60inferred by electronic annotationIEAGOIEAPP2A dephosphorylates RAF1PP2A dephosphorylates RAF1This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>Reactome DB_ID: 293561Reactome DB_ID: 103695141Reactome DB_ID: 103695181p21RAS:GTP:p-S621 RAF1 homo/heterodimer [plasma membrane]p21RAS:GTP:p-S621 RAF1 homo/heterodimerReactome DB_ID: 103695161O-phospho-L-serine at 621 (in Homo sapiens)621EQUAL1EQUAL648EQUALReactome DB_ID: 103068771Converted from EntitySet in ReactomeReactome DB_ID: 103691241Reactome DB_ID: 102989991Reactome Database ID Release 7010369518Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10369518ReactomeR-XTR-56754121Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-5675412.1Reactome DB_ID: 293721PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 10303590PP2A [cytosol]PP2AConverted from EntitySet in ReactomeReactome DB_ID: 103035781PP2A regulatory subunit B56 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityConverted from EntitySet in ReactomeReactome DB_ID: 103035841PP2A-subunit A [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityConverted from EntitySet in ReactomeReactome DB_ID: 103035881PP2A-catalytic subunit C [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityReactome Database ID Release 7010303590Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10303590ReactomeR-XTR-1962061Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-196206.1Reactome Database ID Release 7010369158Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10369158Reactome Database ID Release 7010369520Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10369520ReactomeR-XTR-56754311Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-5675431.1Along with PPP5C-mediated dephophosphorylation of the NtA region, PP2A contributes to the inactivation of RAF1 by mediating the dephosphorylation of AL loop residues. PP2A-mediated dephosphorylation of RAF1 may be stimulated by the prior hyperphosphorylation of RAF1 by MAPKs (Dougherty et al, 2005; reviewed in Matallanas et al, 2011).inferred by electronic annotationIEAGOIEAACTIVATIONReactome Database ID Release 7010369521Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10369521Reactome DB_ID: 10369457O-phospho-L-serine at 621 (in Homo sapiens)621EQUALO4'-phospho-L-tyrosine at 341 (in Homo sapiens)341EQUALO-phospho-L-serine at 338 (in Homo sapiens)338EQUALO-phospho-L-threonine at 491 (in Homo sapiens)491EQUALO-phospho-L-serine at 494 (in Homo sapiens)494EQUALO-phospho-L-serine at 29 (in Homo sapiens)29EQUALO-phospho-L-serine at 43 (in Homo sapiens)43EQUALO-phospho-L-serine at 259 (in Homo sapiens)259EQUALO-phospho-L-serine at 296 (in Homo sapiens)296EQUALO-phospho-L-serine at 301 (in Homo sapiens)301EQUALO-phospho-L-serine at 642 (in Homo sapiens)642EQUAL1EQUAL648EQUAL3.1.3Cytosolic DUSPs dephosphorylate MAPKsCytosolic DUSPs dephosphorylate MAPKsThis event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>Reactome DB_ID: 293561Converted from EntitySet in ReactomeReactome DB_ID: 103694441Converted from EntitySet in ReactomeReactome DB_ID: 103694931MAPK monomers and dimers [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityMAPK3 [cytosol]Reactome DB_ID: 293721PHYSIOL-LEFT-TO-RIGHTACTIVATIONConverted from EntitySet in ReactomeReactome DB_ID: 10369505cytosolic MAPK DUSPs [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityDUSP6 [cytosol]DUSP7 [cytosol]DUSP9 [cytosol]UniProtQ28E94UniProtF6R4B2UniProtF7EIM1GO0008138GO molecular functionReactome Database ID Release 7010369506Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10369506Reactome Database ID Release 7010369508Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10369508ReactomeR-XTR-56753761Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-5675376.1MAPKs are inactivated by dephosphorylation of the activation loop T and Y residues by dual-specificity MAPK phosphatases (DUSPs) (reviewed in Roskoski, 2012b). Cytosolic MAPKs are dephosphorylated by the MAPK-specific class II DUSPs 6,7 and 9, but may also be dephosphorylated by cytosolic forms of class III DUSPs 8, 10 and 16, which preferentially dephosphorylate p38 and JNK MAP kinases (reviewed in Bermudez et al, 2010; Kandoh and Nishida, 2007).17208316Pubmed2007Regulation of MAP kinases by MAP kinase phosphatasesKondoh, KunioNishida, EBiochim. Biophys. Acta 1773:1227-3720463170Pubmed2010The dual-specificity MAP kinase phosphatases: critical roles in development and cancerBermudez, OPagès, GGimond, CAm. J. Physiol., Cell Physiol. 299:C189-20222569528Pubmed2012ERK1/2 MAP kinases: structure, function, and regulationRoskoski, Robert JrPharmacol. Res. 66:105-43inferred by electronic annotationIEAGOIEA3.1.3Nuclear DUSPs dephosphorylate MAPKsNuclear DUSPs dephosphorylate MAPKsThis event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>Converted from EntitySet in ReactomeReactome DB_ID: 103694481nucleoplasmGO0005654p-T,Y MAPK monomers and dimers [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityphospho-p-T185,Y187-MAPK1 [nucleoplasm]phospho-p-T202,Y204-MAPK3 [nucleoplasm]Reactome DB_ID: 293561Reactome DB_ID: 1135501Converted from EntitySet in ReactomeReactome DB_ID: 103694701MAPK monomers and dimers [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityMAPK3 [nucleoplasm]MAPK1 [nucleoplasm]PHYSIOL-LEFT-TO-RIGHTACTIVATIONConverted from EntitySet in ReactomeReactome DB_ID: 10369484nuclear MAPK DUSPs [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityDUSP5 [nucleoplasm]UniProtF6UVL5Reactome Database ID Release 7010369485Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10369485Reactome Database ID Release 7010369487Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10369487ReactomeR-XTR-56753731Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-5675373.1MAPKs are inactivated by dephosphorylation of the activation loop T and Y residues by dual-specificity MAPK phosphatases (DUSPs) (reviewed in Roskoski, 2012b). Class 1 DUSPs, including DUSP 1, 2, 4 and 5 are nuclear and are generally activated by the same extracellular stimuli that promote MAPK signaling, establishing a negative feedback loop. DUSP5 is specific for MAPK3 and 1, while the other class 1 enzymes have broad specificity. Nuclear MAPKs may also be inactivated by nuclear forms of class III DUSPs, including DUSP8, 10 and 16, although the preferred substrate of these enzymes are the p38 and JNK MAP kinases (reviewed in Bermudez et al, 2010; Kondoh and Nishida, 2007).inferred by electronic annotationIEAGOIEABRAP binds KSR1:MARK3BRAP binds KSR1:MARK3This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>Reactome DB_ID: 103692921UniProt:F6QZK6UniProtF6QZK61EQUAL592EQUALReactome DB_ID: 103690971KSR1:MARK3 [cytosol]KSR1:MARK3Reactome DB_ID: 103690951UniProt:F6ZJY0UniProtF6ZJY01EQUAL753EQUALReactome DB_ID: 103690911UniProt:F6RFK5UniProtF6RFK51EQUAL923EQUALReactome Database ID Release 7010369097Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10369097ReactomeR-XTR-56726891Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-5672689.1Reactome DB_ID: 103692941BRAP:KSR1:MARK3 [cytosol]BRAP:KSR1:MARK3Reactome DB_ID: 1036929211EQUAL592EQUALReactome DB_ID: 103690971Reactome Database ID Release 7010369294Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10369294ReactomeR-XTR-56740111Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-5674011.1Reactome Database ID Release 7010369389Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10369389ReactomeR-XTR-56740191Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-5674019.1BRAP is a negative regulator of MAPK signaling that binds KSR1 as assessed by coimmunoprecipitation. This interaction abrogates KSR1 homodimer and KSR1:RAF heterodimer formation, and disrupts the recruitment of MAP2K kinases to RAF (Methany et al, 2004; Chen et al, 2008; reviewed in Methany et al, 2009). BRAP inhibition of KSR1 is relieved in an unknown manner by autoubiquitination after RAS pathway activation (reviewed in Methany et al, 2009).19091743Pubmed2009Signaling threshold regulation by the Ras effector IMPMatheny, Sharon AWhite, Michael AJ. Biol. Chem. 284:11007-1114724641Pubmed2004Ras regulates assembly of mitogenic signalling complexes through the effector protein IMPMatheny, Sharon AChen, ChiyuanKortum, Robert LRazidlo, Gina LLewis, Robert EWhite, Michael ANature 427:256-6018332145Pubmed2008IMP modulates KSR1-dependent multivalent complex formation to specify ERK1/2 pathway activation and response thresholdsChen, ChiyuanLewis, Robert EWhite, Michael AJ. Biol. Chem. 283:12789-96inferred by electronic annotationIEAGOIEABRAP binds RAS:GTPBRAP binds RAS:GTPThis event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>Reactome DB_ID: 1036929211EQUAL592EQUALReactome DB_ID: 103068771Reactome DB_ID: 103693851p21 RAS:GTP:BRAP [plasma membrane]p21 RAS:GTP:BRAPReactome DB_ID: 1036929211EQUAL592EQUALReactome DB_ID: 103068771Reactome Database ID Release 7010369385Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10369385ReactomeR-XTR-56740031Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-5674003.1Reactome Database ID Release 7010369387Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10369387ReactomeR-XTR-56740181Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-5674018.1BRAP is a negative regulator of the RAF/MAPK cascade that inhibits the homo- and heterodimerization of KSR1 and RAF and preventing downstream signal propagation (Matheny et al, 2004; Chen et al, 2008; reviewed in Matheny et al, 2009). Upon RAS stimulation, BRAP binds to RAS:GTP. This stimulates BRAP's E3 HECT ubiquitin ligase activity, promoting its autoubiquitination and thereby relieving the inhibition of KSR1 activity (Matheny et al, 2004; reviewed in Matheny et al, 2009). USP15 is a deubiquitinase that stabilizes BRAP protein levels and thus acts to dampen MAPK signaling (Hayes et al, 2013).23105109Pubmed2012Direct and indirect control of mitogen-activated protein kinase pathway-associated components, BRAP/IMP E3 ubiquitin ligase and CRAF/RAF1 kinase, by the deubiquitylating enzyme USP15Hayes, Sebastian DLiu, HMacDonald, EwanSanderson, Christopher MCoulson, Judy MClague, Michael JUrbé, SylvieJ. Biol. Chem. 287:43007-18inferred by electronic annotationIEAGOIEABRAP autoubiquitinatesBRAP autoubiquitinatesThis event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>Converted from EntitySet in ReactomeReactome DB_ID: 102938551Ub [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityUBB(153-228) [cytosol]UBB(77-152) [cytosol]RPS27A(1-76) [cytosol]UBB(1-76) [cytosol]UBC(229-304) [cytosol]UBC(305-380) [cytosol]UBC(533-608) [cytosol]UBC(457-532) [cytosol]UBA52(1-76) [cytosol]UBC(1-76) [cytosol]UBC(77-152) [cytosol]UBC(381-456) [cytosol]UBC(609-684) [cytosol]UBC(153-228) [cytosol]UniProtF6VNK4UniProtF7EHK8UniProtF7DNS3UniProtQ6AZL4Reactome DB_ID: 103693851Reactome DB_ID: 103693941p21 RAS:GTP:ub-BRAP [plasma membrane]p21 RAS:GTP:ub-BRAPReactome DB_ID: 103068771Reactome DB_ID: 103693921ubiquitinylated lysine at unknown positionubiquitinylated lysine [MOD:01148]Reactome Database ID Release 7010369394Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10369394ReactomeR-XTR-56740051Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-5674005.1PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 10369385GO0061630GO molecular functionReactome Database ID Release 7010369395Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10369395Reactome Database ID Release 7010369397Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10369397ReactomeR-XTR-56740221Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-5674022.1Binding to activated RAS stimulates the ubiquitinase activity of BRAP, promoting autoubiquitination and relieving the inhibition of KSR1 (Methany et al, 2004; Chen et al, 2008; Methany et al, 2009).inferred by electronic annotationIEAGOIEAReactome Database ID Release 7010400142Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10400142ReactomeR-XTR-56752211Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-5675221.1The duration and extent of activated MAPK signaling is regulated at many levels through mechanisms that include phosphorylation and dephosphorylation, changes to protein interacting partners and subcellular localization (reviewed in Matallanas et al, 2011). <br><br>Activated RAF proteins are subject to MAPK-dependent phosphorylation that promotes the subsequent dephosphorylation of the activation loop and NtA region, terminating RAF kinase activity. This dephosphorylation, catalyzed by PP2A and PP5, primes the RAF proteins for PKA or AKT-mediated phosphorylation of residues S259 and S621, restoring the 14-3-3 binding sites and returning the RAF proteins to the inactive state (von Kriegsheim et al, 2006; Dougherty et al, 2005; reviewed in Matallanas et al, 2011). The phosphorylated RAF1 NtA is also subject to additional regulation through binding to the PEBP1 protein, which promotes its dissociation from MAP2K substrates (Shin et al, 2009). <br><br>Activated MAPK proteins also phosphorylate T292 of MAP2K1; this phosphorylation limits the activity of MAP2K1, and indirectly affects MAP2K2 activity through by modulating the activity of the MAP2K heterodimer (Catalanotti et al, 2009; reviewed in Matallanas et al, 2011).<br><br>Dephosphorylation of MAPKs by the dual specificity MAPK phosphatases (DUSPs) plays a key role in limiting the extent of pathway activation (Owens et al, 2007; reviewed in Roskoski, 2012b). Class I DUSPs are localized in the nucleus and are induced by activation of the MAPK pathway, establishing a negative feedback loop, while class II DUSPs dephosphorylate cytoplasmic MAPKs (reviewed in Rososki, 2012b).<br>MAPK signaling is also regulated by the RAS GAP-mediated stimulation of intrinsic RAS GTPase activity which returns RAS to the inactive, GDP bound state (reviewed in King et al, 2013).23443682Pubmed2013Nonredundant functions for Ras GTPase-activating proteins in tissue homeostasisKing, Philip DLubeck, Beth ALapinski, Philip ESci Signal 6:re117496916Pubmed2007Differential regulation of MAP kinase signalling by dual-specificity protein phosphatasesOwens, D MKeyse, S MOncogene 26:3203-13inferred by electronic annotationIEAGOIEA