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RAS activates ERK. 1000 / 1309
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"Subsequent studies using these cell systems revealed that another potent inhibitor, gliotoxin, as well as the CMLD 7877 compound, which displayed binding to the CRAF-RBD at high concentrations in the SPR analysis, could also inhibit RAS-dependent ERK activation ( xref and xref )."
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"As already outlined above, the disturbed intracellular Ca 2+ signaling could be a primary event in ADPKD and may be responsible for the switch to a proliferative phenotype with an elevation in B-Raf protein levels and cAMP stimulated, Ras dependent activation of B-Raf and ERK [XREF_BIBR, XREF_BIBR]."
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"Ras is known to activate ERK1/2 in the MAPK signaling pathway [34], and it is therefore suggested that the reduction of Ras expression by nanaomycin K may be one of the mechanisms by which it inhibits the activation of the MAPK signaling pathway.In animal experiments, nanaomycin K had an inhibitory effect on tumor growth compared to controls, without any adverse effects."
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"However, further tests will be needed to confirm whether there is indeed a relationship between the mutational status of p53 and the therapeutic efficiency of Eph inhibitors.Approximately 30% to 50% of CRCs express a mutated RAS gene that promotes the constitutive activation of the ERK/MAPK downstream signaling pathway [37]."
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"In breast cancer cells, targets are fibronectin stimulated FAK signaling and ERK1/2 activation 109, inhibition of beta-catenin activation by targeting the receptor-type protein tyrosine phosphatase kappa 110, inhibition of Ras signaling by direct targeting of Hsp70 and Raf leading to reduced ERK1/2 activation 111, inhibition of CIN-85-mediated invasion 112, and inhibition of proliferation and stimulation of apoptosis in vivo 88."
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"In the absence of oncogenic Ras and Raf mutations, other oncogenic events that engage the Ras and MAPK pathway are also likely to stimulate normal feedback mechanisms that may increase the activity of various intermediaries in the Ras and MAPK signalling module, thereby promoting the ongoing activation of ERK kinase signalling."
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"A dominant negative form of RHAMMv4 inhibits mutant active Ras activation of ERK and coimmunoprecipitates with both mitogen activated protein kinase kinase and ERK, suggesting that the intracellular RHAMMv4 acts downstream of Ras, possibly at the level of mitogen activated protein kinase kinase-ERK interactions."
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"30 The efficacy of sorafenib has been demonstrated in plenty of clinical studies since it was approved by the FDA as the first-line treatment of HCC in 2007.9,31,32 Sorafenib inhibits retrovirus-associated DNA sequence protein (RAS)/rapidly accelerated fibrosarcoma protein (RAF)/mitogen activation and extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathways.33,34 However, the resistance of sorafenib limits its long-term anticancereffect."
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"Research has shown that mutations in Ras signaling pathway-related genes (such as NRAS and KRAS) can activate mitogen-activated extracellular signal-regulated kinase (MEK) and its downstream pathways, leading to excessive tumor cell proliferation and low PLT levels.7 8 Trametinib, a specific MEK inhibitor, is commonly used to treat unresectable or metastatic melanomas harboring BRAFV600E and V600K mutations."
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"To investigate the specific role of A-Raf in this process we generated A-Raf deficient mouse embryonic fibroblasts (MEFs) and embryonic stem (ES) cells by gene targeting and characterized their ability to undergo proliferation, differentiation, apoptosis, ERK activation, and transformation by oncogenic Ras and Src."
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"Collectively, they are found in a set of important pathways such as the Ras driven Erk1/2 and phosphatidylinositol 3-kinase-Akt signaling, those mediated by receptor tyrosine kinases (RTK), or those that are involved in cell cycle and apoptosis, DNA damage control, chromatin modification, and transcriptional regulation [XREF_BIBR], [XREF_BIBR]."
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"We studied the Shc adaptor proteins p52 and p46Shc, which can activate the RAS and Mitogen Activated Protein kinase pathway, p66Shc which is uncoupled from RAS and MAP kinases and the MAP kinase family members Extracellular signal Regulated Kinase (ERK) and c-Jun NH2-terminal protein Kinase (JNK) or Stress Activated Protein Kinase (SAPK)."
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"Intracellular signals involving the activation of numerous members such as the PKC family and phospholipase D activate small GTPases like Rac, Ras, and Rho, which in turn induce the activation of extracellular signal-regulated kinase (Erk), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinases (MAPKs)."
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"Using an optogenetics-driven MAPK activation approach in cultured mammalian cells, it was revealed that distinct Ras/MAPK regulation (such as a paracrine STAT3 circuit) can distinguish between biochemical signaling outputs, namely sustained (strong) or transient (weak) Erk activation by Ras [ xref ]."
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"For instance, the extracellular signal-regulated kinase (ERK)- mitogen activated protein kinase (MAPK) signaling pathway, which is activated by the RAS oncoproteins (HRAS, KRAS, and NRAS) and positively associated with cell proliferation and survival [36,37], has been shown to promote the Warburg effect [38]."
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"In pancreatic cancer, the inhibitor of NF-kappaB kinase alpha (IKKalpha) forms complexes with Smads and transactivates the Snail1 and Snail2 genes that elicit EMT [XREF_BIBR], whereas the Ras oncoprotein promotes Erk MAP-kinase signaling that also contributes to Snail1 induction [XREF_BIBR]."
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"RAGE attaches to oxidized LDL, which acts as a ligand affecting downstream genes including PKC activation, mitogen-activated protein kinase (MAPK), Ras-mediated extracellular signal-regulated kinase (ERK1/2), p38, stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and Janus kinase signal transducer and activator of a transcription (JAK/STAT) pathway that activates STAT3, NFκB, AP-1 and HIF-1α [85,86,87]."
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"Accordingly, it is highly conceivable that METH could increase ROS levels and subsequently induce Ras expression, to activate the MEK/ERK signaling pathway in liver cancer cells.Importantly, it should also be borne in mind that NAC could also be used against the progression and migration of cancer, irrespective of METH use (29, 30)."
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"Activated Ras enhanced ERK1/2 dependent b-catenin transactivation for the Warburg effect, tumor cell proliferation, and brain tumorigenesis.the cell cycle progression, the Warburg effect, tumor cell proliferation, and brain tumorigenesis in mice.7 Given that FAM129B has been found highly expressed in many types of cancers, the identification of the essential function of FAM129B in activation of Ras and subsequent regulation of the Warburg effect and tumor cell proliferation provides new approaches to disrupt the oncogenic signaling from growth factor receptors and Ras for cancer treatment.Disclosure of potential conflicts of interestNo potential conflicts of interest were disclosed.References [1] Yang W, Lu Z. Cell Cycle 2013; 12:3154-8; PMID :24013426; http://dx."
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"As already outlined above, the disturbed intracellular Ca 2+ signaling could be a primary event in ADPKD and may be responsible for the switch to a proliferative phenotype with an elevation in B-Raf protein levels and cAMP-stimulated, Ras-dependent activation of B-Raf and ERK [ xref , xref ]."
eidos
"Up to half of the patients diagnosed with CM carry activating mutations in the serine-threonine kinase of the BRAF gene ( BRAF-V600 ) , with almost a quarter of patients ( 15-25 % ) carrying mutations in the RAS gene ( Q61R , Q61K ) , which downstream activate RAF , MEK , and ERK ."
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"Then, it triggers a variety of downstream effectors, including mitogen-activated protein kinase (MAPK), p38, Ras-mediated extracellular signal-regulated kinase (ERK1/2), Janus kinase signal transducer and activator of transcription (JAK/STAT), and the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) pathway, that in turn will lead to sustained activation of transcription factors such as NF-κB, HIF-1α, STAT3, and AP-1 [5]."
| PMC
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"These results suggest two possible Erk activation mechanisms, or combinations thereof : Ras and PI3K promote Erk signaling independently, or PI3K lies upstream of Ras in the same pathway, in which case at least one additional pathway would be responsible for the residual Erk phosphorylation seen when either Ras or PI3K is inhibited."
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"However, Ras inhibitor manumycin A, MEK inhibitor PD 98059, PI3K inhibitor wortmannin, NF-kB inhibitor PDTC and 3-MA reversed the protective effect of silibinin, indicating that Ras, ERK, PI3K and NF-kB exerted a protective effect.Western blot analysis indicated that the inhibition of Ras by manumycin A inhibited the enhancement of Raf-1 and ERK and the conversion of NF-kB from cytosol to nuclear was also inhibited."
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"Upon ligand binding, RAGE activates multiple intracellular signaling pathways involving in the small guanine nucleotide triphosphatases (GTPases) ras related C3 botulinum toxin substrate 1 (Rac1)/cell division control protein 42 (Cdc42), Ras mediated extracellular signal regulated kinase 1/2 (ERK1/2), Phosphoinositide 3-kinase (PI3-K)/Akt, stress activated protein kinase and c-Jun-NH 2-terminal kinase (SAPK and JNK), p38 mitogen activated protein kinase (MAPK), NF-kappaB and caspases [XREF_BIBR]."
| PMC
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"In LbetaT2 cells, Pyk2 was shown to act as a scaffold for the assembly of a signaling complex containing c-Src, Grb2, and Sos, and this complex was suggested to form a direct link between GnRH induced calcium currents and canonical Ras dependent activation of the ERK pathway [XREF_BIBR]."
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"Collectively, these results are consistent with the notion that the heightened PDE activity detected in asthmatic HASM cells is partly, but significantly, attributed to constitutively increased co-localization of Rap1GAP with Gα, a phenomenon that is ostensibly permissive of Gi-βγ-stimulated Ras-induced ERK1/2 activation consequent to inactivation of Rap1 by Rap1GAP."
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"These observations place PKNs downstream of PI3K, PDK1, and mTOR suggesting that PKNs may receive multiple PI3K-dependent inputs.The biological responses downstream to the interaction of chemoattractants with FPRs are regulated by Ras and Rho GTPases family, which induce the activation of PI3K, AKT and ERK1/2 [65,66,67]."
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"For instance, the binding of platelet derived growth factor (PDGF) to its specific receptor tyrosine kinase (RTK) at the surface of the VSMC membrane activates ras, which triggers the extracellular signal regulated kinase (Erk)/mitogen-activated protein kinase (MAPK) signal transduction, resulting in cell cycle suppression by inactivating MYT1, which restrains cell cycle progression, accelerating p27Kip1 degradation to activate cyclin E/Cdk2 and inducing cyclin D1 transcription to raise DNA synthesis by regulating Cdk4 and Cdk6."
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"Wen et al [XREF_BIBR] have shown that ERK1/2 activation in response to suboptimal stimulation of thymocytes is dependent on Ins (1,4,5) P 3 3-kinase B; they propose a model in which Ins (1,4,5) P 3 3-kinase B dependent production of Ins (1,3,4,5) P 4 acts to sequester an Ins (1,3,4,5) P 4 -binding GTPase activating protein 1 [XREF_BIBR], promoting Ras dependent activation of ERK1/2."
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"RAS gene mutations, V599E gene mutations in BRAF genes, and overexpressed receptor tyrosine kinases (RTKs) could activate RAS, and the activated RAS further activates the cascade of RAF/ERK signaling pathway, bringing growth factor signals into the nucleus, thereby playing a role in regulating gene transcription and promoting cell proliferation."
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"The CAM-dependent step in the Erk1/2 activation cascade is downstream of Ras activation, because inhibitors of CAM antagonize Erk1/2 activation induced by constitutively activated mutants of Ras and c-Src but not by constitutively activated mutants of Raf and MEK (mitogen and extracellular signal-regulated kinase)."
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"This activation involves a variety of downstream effectors, including mitogen-activated protein kinase (MAPK), p38, stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), Ras-mediated extracellular signal-regulated kinase (ERK1/2), and Janus kinase signal transducer and activator of transcription (JAK/STAT) pathway which will sequentially lead to sustained activation transcription factors, such as NF-κB, STAT3, HIF-1α, and AP-1 [74,80,81]."
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"Ras dependent activation of the ERK MAP kinase pathway does seem to be required for proliferation of Rb-/- MEFs, as we have observed that DNA synthesis in Rb-/- MEFs is as sensitiveto PD 098059, an inhibitor of the ERK activator MEK [22], as are Rb +/- cells (S.M., unpublished data)."
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"In contrast, the same drugs efficiently inhibited Ras induced ERK1/2 phospshorylation in rat brain neuroblasts [XREF_BIBR], as well as geranylgeranylation of Rho family GTPase in neurons [XREF_BIBR], leading to an increase in apotosis and tau phosphorylation, respectively [XREF_BIBR, XREF_BIBR] (XREF_FIG)."
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"In XREF_FIG, Ras increased by -fold from to; ERK and MYC increased by -fold from to and from to, respectively; miR-9 increased by -fold from to; MMP increased by -fold from to compared to their values in normal cells; SOS decreased by -fold from to; let-7 decreased by -fold from to, and E-Cadherin decreased by -fold from to."
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"Activation of NFAT requires dephosphorylation by the calcium mediated calcineurin phosphatase to promote NFAT nuclear accumulation, and the Ras activated extracellular signal regulated kinase (ERK) mitogen activated protein (MAP) kinase, which targets NFAT partners, to potentiate transcription."
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"In various cell types activation of Ras leads to activation of the mitogen activated protein kinases (MAPKs), extracellular signal regulated kinase 1/2 (ERK1/2), and protein kinase B (PKB)/Akt, which exert opposing effects on adipogenesis, with ERK1/2 inhibiting and PKB and Akt promoting terminal differentiation."
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"A 15-/xl aliquot of fraction 44 from the Mono S column chromatography was assayed with the indicated amounts of the GTPyS-bound form of lipid-modified or unmodified Ki-Ras. (e) With lipidmodified Ki-Ras; (O) with lipid-unmodified Ki-Ras.
[27]
USE OF SEMIINTACT MAMMALIAN CELLS
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Several groups have reported that lipid-unmodified Ras activates ERK in cell-free systems using crude lysates."
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"We also examined the phosphorylation of Akt at S473 and T308 and found that phosphorylation of Akt at these sites were not significantly increased by electrical stimulation (Additional file 3 : Figure S2E-H), suggesting that the signaling in response to repetitive stimulation is primarily through Ras and Raf activation of ERK1/2."
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"Consequently, due to the importance of RAS activated RAF --> MEK --> ERK signaling in PDA, we examined in more depth the effects of mitogen activated protein and extracellular signal regulated kinase 1/2 (MEK1/2) inhibition on patterns of mRNA expression in vitro and in vivo using a panel of PDA cell lines."
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"Finally, together with increased PDE activity attributed to free Gbetagamma regulated ERK1/2 activation, the results demonstrated that asthmatic HASM cells also exhibit markedly increased direct binding of the small Rap1 GTPase activating protein (Rap1GAP) to the alpha-subunit of G protein, a phenomenon that serves to cooperatively facilitate Ras induced ERK1/2 activation, thereby enabling enhanced Gbetagamma regulated PDE activity."
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"The multiple protein binding domains in the Iqgap protein afford the tethering of signalling pathway components, which increases efficiency of complex formation and signalling intensity. xref Many key components of cell signalling, such E-cadherin, β-catenin, calmodulin and ERK, have been identified as Iqgap binding partners. xref Of note, Iqgap3 specifically interacts with the active, GTP-bound form of Ras, and through Ras-dependent Erk activation, constitutes an essential aspect of cell proliferation. xref Moreover, IQGAP3, alone in the IQGAP family, is indispensable for cell proliferation and motility during zebrafish embryonic development. xref IQGAP3 functions downstream of FGFR1-Ras signalling to regulate proliferation during zebrafish embryogenesis. xref "
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"The canonical ERK1/2 signaling pathway initiates when an extracellular ligand binds a receptor tyrosine kinase, usually a growth factor receptor, leading to activation of Ras which promotes Raf serine/threonine kinase activity and sequential activation of MEK1/2 and ERK1/2 by phosphorylation [7]."
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"It was also proposed that a molecular mechanism in which the persistent venous hypertension (via pressure mediated mechanotransduction) could stimulate Ras production, which in turn would activate MAPK and Erks, and hence inhibit TGF-beta1 regulated matrix contraction (resulting in prolonged wound healing) [XREF_BIBR]."
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"Considering the positive role of Shp2 in Ras-dependent Erk activation (Ras-to-Erk), as well as in oncogenic Ras-to-Erk [ xref , xref ] and target therapy resistance [ xref ], small molecules to inhibit the bivalent roles of Shp2 have been developed as novel anti-cancer therapeutic agents [ xref ]."
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"Collectively, these results are consistent with the notion that the heightened PDE activity detected in asthmatic HASM cells is partly, but significantly, attributed to constitutively increased co-localization of Rap1GAP with Galpha, a phenomenon that is ostensibly permissive of Gi-betagamma-stimulated Ras induced ERK1/2 activation consequent to inactivation of Rap1 by Rap1GAP."
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"AGEs/RAGE interaction triggers a variety of downstream effectors including mitogen-activated protein kinase (MAPK), p38, stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), Ras-mediated extracellular signal-regulated kinase (ERK1/2), and Janus kinase signal transducer and activator of transcription (JAK/STAT) pathway that in turn will lead to sustained activation transcription factors such as NF-κB, STAT3, HIF-1α, and AP-1 [25,49,50]."
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"While our present results are consistent with the prevailing concept that GPCR dependent and receptor independent stimulation of Ras mediated ERK1/2 activation uses proximal signals generated by Gbetagamma coupled c-Src activation [XREF_BIBR - XREF_BIBR], our data also concur with established evidence domonstrating that : 1) ERK1/2 activation is suppressed by recruitment of the GTP binding protein, Rap1, which inhibits Ras function (36-38) : and 2) this suppression is reversed by membrane recruitment of Rap1GAP, a GTPase which also acts as a GDI that binds via its GoLoco motif to the alpha-subunit of Gi protein, thereby inhibiting Rap1 activity [XREF_BIBR - XREF_BIBR]."
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"XREF_BIBR Recent studies have suggested that merlin can regulate multiple pathways implicated in tumorigenesis including retrovirus associated DNA sequences (Ras)/rapidly accelerated fibrosarcoma (Raf)/mitogen extracellular signal regulated kinase (MEK)/extracellular-signal-regulated kinases (ERK), mammalian target of rapamycin complex 1 (mTORC1), Rac and p21 activated kinase (PAK)/C-Jun kinase, phosphoinositide 3-kinase (PI3K)/Akt and the intranuclear E3 ubiquitin ligase CRL4 (DCAF1) (XREF_FIG)."
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"RAS proteins require post-translational modification by farnesylation, adding a farnesyl isoprenoid moiety catalyzed by farnesyltransferase (FTase) to be biologically active. xref This ensures the exact localization of RAS proteins at the inner surface of the plasma membrane, thus enabling them to recruit their target enzymes and initiate the signaling. xref , xref Upon activation, RAS induces numerous downstream proteins, such as Raf-1/mitogen-activated protein kinase pathway, phosphoinositide-3 kinase (PI3K), as well as the GEFs for the RAS-like (Ral) small GTPases (RalGEFs) and the Rac/Rho pathway. xref Aberrant activation of RAS could lead to irregular cellular events such as cell proliferation, differentiation, and cancer. xref , xref Alteration of the RAS-MAPK pathway due to mutations in RAS or RAF genes has been very often reported. xref RAS also activates BRAF, MEK1, and ERK, which regulate the transcription of genes that promote cancer."
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"We would predict that oncogenic Ras pathway mutations (e.g. at EGFR, Ras or Raf) would induce nuclear Erk activity that would still be subject to DUSP mediated adaptation and thus drive a brief transcriptional pulse, providing a valuable brake on sustained growth promoting gene activation."
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"If a KSR mutant protein fails to facilitate Ras mediated ERK activation, it may be due to an inability to translocate from the cytoplasm to the plasma membrane in a regulated manner, as is the case for KSR proteins in which the structure of the atypical C1 domain has been disrupted."
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"For instance, in mammary epithelial cells, depleting Crb or Pals caused dephosphorylation and nuclear translocation of YAP, which is a crucial step for the inhibition of the Hippo signalling pathway and results in increased cell proliferation. xref , xref In a DMBA/TPA‐induced skin cancer model, the loss of Par3, aPKC or both, strongly reduced tumour size and multiplicity, mainly via impairing the activation of ERK1/2 and Akt by Ras. xref In mammary epithelia, dysregulation of Scrib prevented Myc‐induced apoptosis and promoted epithelial‐mesenchymal transition (EMT) and tumorigenesis. xref , xref The effects of cell polarity disruption on tumour growth rely on the association and regulation of downstream signalling pathways. xref , xref Besides, the roles of polarity proteins in tumorigenesis seem complicated, displaying either pro‐ or anti‐tumorigenic functions and largely depending on the context of the cells. xref , xref , xref "
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"Thus, these observations are most consistent with a model wherein a single p53-mutant neural stem cell spontaneously loses Nf1 or acquires other oncogenic mutations, activating Ras mediated Erk and MAPK signaling pathway and promoting clonal expansion of p-Erk + Olig2 + p53 Mutant -expressing glioma precursors."
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"NFLS belongs to the group of phenotypically overlapping neuro-cardio-facial-cutaneous syndromes that are all caused by germ line mutations in genes of the Ras/mitogen-activated protein kinase extracellular signal-regulated kinase (ERK) pathway and that present with some degree of learning difficulties or mental retardation."
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"Another study determined that H O -induced oxidative stress increases WNT/β-catenin signaling and directly affects the intracellular signaling machinery in NIH3T3 cells, where NXN overexpression selectively suppresses WNT/β-catenin pathway but its ablation by a RNAi results in TCF activation, accelerated cell proliferation, and enhanced oncogenicity through cooperation with either mitogen-activated extracellular signal-regulated kinase kinase (MEK) or Ras [8]."
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"Transient expression of 12D2, 12D3, and 12D4 potently inhibited KRAS(G12D)-mediated activation of ERK–MAPK, but was ineffective at inhibiting ERK activation by KRAS(G13D) and KRAS(G12R), as well as epidermal growth factor (EGF)-induced ERK activation mediated by wild-type RAS (Fig. 6 C–F)."
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"Ras associates with TLR2 and activates the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (ERK), whereas tumor necrosis factor receptor-associated factor 6 (TRAF6)/transforming growth factor beta-activated kinase 1 (TAK1)-dependent signaling activates p38 MAPK."
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"Ras could activate the ERK signaling pathway and cause rapid cell proliferation.20 Rho and Cdc42 could enhance cell migration and invasion by regulating cytoskeletal rearrangement.21 Moreover, in our study, SQLE was observed to activate ERK signaling, which has been reported as an effector of the mevalonate pathway."
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"The major findings of this study are as follows : (1) Statins reduce aneurysm formation primarily via inhibition of Ras prenylation, (2) Ras prenylation reduction decreases downstream ERK signaling, and (3) statin mediated attenuation of Ras signaling correlates with inhibition of ERK dependent MMP activation."
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"Subsequently, calmodulin-dependent protein kinase II (CaMKII) is triggered, and then SynGAP is phosphorylated, further negatively regulating Ras-mediated ERK/MAPK signaling cascades and restraining AMPAR insertion at the postsynaptic membrane (Jeyabalan and Clement, 2016; Meili et al., 2021)."
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"The Ras dependent activation of Erk kinases by G protein coupled receptors (GPCRs) is thought to involve tyrosine phosphorylation of docking proteins that serve as scaffolds for the plasma membrane recruitment of Ras guanine nucleotide exchange factors, such as the Grb2 and mSos complex."
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"As shown in xref , unlike wild-type NgBR-HA ( xref , lane 4) or NgBR(L186)-HA mutant ( xref , lane 6), which does not lose the binding to Ras ( xref , lane 2 and 3), NgBR(E262)-HA and NgBR(TM)-HA mutants ( xref , lane 8 and 10), which lose the binding to Ras ( xref , lane 4 and 5), cannot increase EGF-stimulated Ras activation and phosphorylation of Akt and ERK in NIH-3T3 cells ( xref , lane 8 and 10)."
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"This cascade includes the initial Ras activated kinase RAF-1 [XREF_BIBR], a mitogen activated protein kinase kinase kinase; MEK, an intermediate mitogen activated protein kinase kinase; and ERK, a mitogen activated protein kinase, which phosphorylates multiple target proteins in cytosol and nucleus."
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"As in growth factor regulated ERK activation, 5-HT1AR-induced ERK activation is mediated by the small GTPases Ras and Raf [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR] and active MEK [XREF_BIBR], a signal cascade that requires the calmodulin dependent endocytosis of receptors as an intermediate step [XREF_BIBR]."
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"PKCα-mediated growth inhibition in these cells involved RAS- and RAF-independent activation of MEK/ERK (Wen-Sheng, 2006) and ERK-dependent induction of miR-101, which targets two subunits of the PRC2 methyltransferase complex, enhancer of zeste homolog 2 (EZH2) and embryonic early development (EED), reducing methylation of histone 3 lysine 27 to regulate gene expression (Chiang et al., 2010)."
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"21 The PI3K/AKT pathway in the central and peripheral nervous system also mediates pain hypersensitivity induced by nerve injury, incision, or inflammation.22,23 Previous studies have demonstrated that CXCR3 activates several intracellular kinases, such as Ras/ERK and PI3K/AKT.24,25 Intrathecal injection of CXCL10 induces rapid ERK activation in the spinal cord."
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"Our study demonstrates that RasGRP3, a regulator of both Ras and Rap1, negatively regulates the production of proinflammatory cytokines (especially IL-6) by activating Rap1 and inhibiting ERK1/2 activation in response to low levels of TLR agonists, which may serve as an early regulatory machinery to limit inflammatory response of macrophages to feeble infection."
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"The largely presynaptic p75NTR [XREF_BIBR] serves dual roles in that it modulates Trk receptor binding and is involved in prolonged Ras mediated activation of ERK and neurite outgrowth [XREF_BIBR], though p75NTR induced neurite outgrowth ceases after prolonged p75NTR activation [XREF_BIBR]."
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"Since the ability of oncogenic RAS to activate ERK alters gene transcription and activates proteins that increase cell growth and survival (2), we determined whether ERK activation was required for the increased Survivin expression observed in PDAC cells expressing mutant forms of KRAS."
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"When mTORC1 is inhibited by rapamycin or its derivatives (rapalogs), this negative-feedback loop is disrupted, leading to activation of PI3K and its effector Akt. xref PI3K can then act on Ras to promote Ras-dependent ERK activation. xref The binding of Ras to PI3K activates the EGFR- and FGF2-signalling pathways."
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"Evidence has also shown that cAMP-mediated cell growth inhibition depends on cAMP-mediated activation of Ras-association proximate 1 (Rap1), which is a small G protein that interacts with Raf-1, preventing Ras-induced ERK activation and finally inhibiting cell proliferation [ xref ]."
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"It is thought to affect RAS loading via its activity on RAS-GAP recruitment to RTK complexes (Montagner et al., 2005) via direct recruitment of Grb2 (Ran et al., 2016), dephosphorylation of RAS on a conserved Tyr32 residue increasing RAS-RAF association and subsequent MEK/ERK signaling (Kano et al., 2019), or via its effect on SRC (Zhang et al., 2004)."
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"Accordingly, while Ras-GTP is normally detected in BDNF treated cells, no Ras-GTP could be detected in striatal STHdh Q111 cells upon BDNF treatment, and transfection of the cells with constitutively active Ras restored ERK activation [XREF_BIBR] further underscoring the selective effect of Htt insult on the ERK pathway in striatal cells."
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"Whereas moderate ras activities only stimulated the mitogenic MEK-ERK pathway, high intensity ras signals induced MEK and ERK to higher levels, leading to stimulation of the MKK3/6-p 38 pathway, which had been shown previously to act downstream of Ras-MEK to trigger the senescence response."
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"In the case of the perturbation of IRS and RAF, GS and RAS were down-regulated due to the decay weights, whereas GS and RAS were up-regulated when we amplified signal flows by adjusting four weights : the negative feedbacks of ERK (ERK to GS and ERK to GAB1), and AKT cascade (PI3K to PIP3 and PIP3 to IRS)."
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"The presented hMEC model was interrogated to ensure that it is able to reproduce some of the known global biological phenomena as previously observed experimentally (XREF_FIG), including EGF induced activation of Akt and Erk, EGF independent regulation of Erk via activated Ras, integrin dependent stimulation of Erk, Rac, and Cdc42, G protein Coupled Receptor activation of adenylyl cyclase, as well as ErbB receptor dimerization hierarchy."
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"The RAS activated RAF --> MEK --> extracellular signal regulated kinase (ERK) and phosphatidylinositol 3 '-kinase (PI3 '-kinase) --> PDK1 --> AKT signaling pathways are believed to cooperate to promote the proliferation of normal cells and the aberrant proliferation of cancer cells."
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"T cells from aged SPA-1-/- mice with high amounts of Rap1GTP showed normal or even enhanced Ras activation with little extracellular signal regulated kinase activation in response to anti-CD3 stimulation, indicating that excess Rap1GTP induced the uncoupling of Ras mediated extracellular signal regulated kinase activation."
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"In addition, treatment of MCF10A cells with the MEK inhibitor U0126 was found to have similar effects on p120-catenin phosphorylation and binding to E-cadherin as did Shoc2 depletion (XREF_FIG), suggesting the need for localized ERK cascade signaling induced by the active M, Ras, and Shoc2 complex."
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"In the light of MAPK signal pathways mediating nuclear translocation of NF-kappaB, which is required for its transcription activity, and galectin-1 directly interacting with Ras, which subsequently activates Erk1/2 and P38 mitogen activated protein kinase (MAPK) signal pathways [XREF_BIBR - XREF_BIBR], we proposed that the mechanisms of galectin-1 inducing MDR1 expression may involve MAPK signal activation and NF-kappaB translocation."
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"The first is through the PI3K/Akt pathway, which is involved in cell survival; the second is through the phospholipase C pathway, which activates protein kinase C and CAMK, which is involved in neuroplasticity; and the third pathway is through Ras, which activates extracellular signal-regulated kinase, which is involved in plasticity, survival, and growth23."
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"Upon ligand binding, the cytoplasmic domain of RAGE acts similarly as do membrane TLRs, recruiting the adaptor proteins diaphanous homolog 1, Toll/interleukin-1 receptor domain-containing adaptor protein, and MyD88 to activate numerous intracellular effector signals, including Ras-related C3 botulinum toxin substrate 1 (Rac1)/cell division control protein 42 (Cdc42), Ras-mediated extracellular signal-regulated kinase 1/2 (ERK1/2), phosphoinositide 3-kinase (PI3K)/Akt, stress-activated protein kinase/c-Jun-NH2-terminal kinase, p38 mitogen-activated protein kinase (MAPK), NF-κB, and caspases (Hudson and Lippman, 2018)."
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"Earlier in vitro studies done with ectopic rLOX-PP expression in cancer cell lines indicate that LOX-PP inhibits Ras mediated activation of Erk1/2 by inhibiting FGF-2 to FGFR1 receptor binding and activation, and by direct interaction with Hsp70 and c-Raf XREF_BIBR, XREF_BIBR, XREF_BIBR."
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"These important differences in synaptic distribution for the two main Ras isoforms in the brain support the notion that they may fulfill distinct synaptic functions.Perhaps one of the most established synaptic functions of Ras is to support Erk activation during LTP (Zhang et al, 2018; Zhu et al, 2002; Araki et al, 2015)."
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"The Rat sarcoma virus (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated extracellular signal-regulated kinase (MEK)/extracellular signal regulated kinase (ERK)/signaling pathway is a well-known signaling pathway that regulates cell survival, growth, and proliferation in normal cells and cancer cells."
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"Overexpression of NRX selectively suppresses the Wnt-beta-catenin pathway and ablation of NRX by RNA-interference (RNAi) results in activation of TCF, accelerated cell proliferation and enhancement of oncogenicity through cooperation with mitogen activated extracellular signal regulated kinase kinase (MEK) or Ras."