| Target General Infomation |
| Target ID |
T23276
|
| Former ID |
TTDR00373
|
| Target Name |
Mitogen-activated protein kinase 3
|
| Gene Name |
MAPK3
|
| Synonyms |
ERK-1; ERT2; Extracellular signal-regulated kinase 1; Insulin-stimulated MAP2 kinase; MAP kinase 1; MAPK 1; Microtubule-associated protein-2 kinase; P44 Mitogen-activated protein kinase; P44-ERK1; P44-MAPK; MAPK3
|
| Target Type |
Clinical Trial
|
| Disease |
Cancer [ICD9: 140-229; ICD10: C00-C96] |
|---|
|
Restenosis [ICD10: I51.89] |
|
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48] |
| Function |
Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK1/ERK2 and MAPK3/ERK1 are the 2 MAPKs which play an important role in the MAPK/ERK cascade. They participate also in a signaling cascade initiated by activated KIT and KITLG/SCF. Depending on the cellular context, the MAPK/ERK cascade mediates diverse biological functions such as cell growth, adhesion, survival and differentiation through the regulation of transcription, translation, cytoskeletal rearrangements. The MAPK/ERK cascade plays also a role in initiation and regulation of meiosis, mitosis, and postmitotic functions in differentiated cells by phosphorylating a number of transcription factors. About 160 substrates have already been discovered for ERKs. Many of these substrates are localized in the nucleus, and seem to participate in the regulation of transcription upon stimulation. However, other substrates are found in the cytosol as well as in other cellular organelles, and those are responsible for processes such as translation, mitosis and apoptosis. Moreover, the MAPK/ERK cascade is also involved in the regulation of the endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC); as well as in the fragmentation of the Golgi apparatus during mitosis. The substrates include transcription factors (such as ATF2, BCL6, ELK1, ERF, FOS, HSF4 or SPZ1), cytoskeletal elements (such as CANX, CTTN, GJA1, MAP2, MAPT, PXN, SORBS3 or STMN1), regulators of apoptosis (such as BAD, BTG2, CASP9, DAPK1, IER3, MCL1 or PPARG), regulators of translation (such as EIF4EBP1) and a variety of other signaling-related molecules (like ARHGEF2, FRS2 or GRB10). Protein kinases (such as RAF1, RPS6KA1/RSK1, RPS6KA3/RSK2, RPS6KA2/RSK3, RPS6KA6/RSK4, SYK, MKNK1/MNK1, MKNK2/MNK2, RPS6KA5/MSK1, RPS6KA4/MSK2, MAPKAPK3 or MAPKAPK5) and phosphatases (such as DUSP1, DUSP4, DUSP6 or DUSP16) are other substrates which enable the propagation the MAPK/ERK signal to additional cytosolic and nuclear targets, thereby extending the specificity of the cascade.
|
| BioChemical Class |
Kinase
|
| UniProt ID |
|
| EC Number |
EC 2.7.11.24
|
| Sequence |
MAAAAAQGGGGGEPRRTEGVGPGVPGEVEMVKGQPFDVGPRYTQLQYIGEGAYGMVSSAY
DHVRKTRVAIKKISPFEHQTYCQRTLREIQILLRFRHENVIGIRDILRASTLEAMRDVYI
VQDLMETDLYKLLKSQQLSNDHICYFLYQILRGLKYIHSANVLHRDLKPSNLLINTTCDL
KICDFGLARIADPEHDHTGFLTEYVATRWYRAPEIMLNSKGYTKSIDIWSVGCILAEMLS
NRPIFPGKHYLDQLNHILGILGSPSQEDLNCIINMKARNYLQSLPSKTKVAWAKLFPKSD
SKALDLLDRMLTFNPNKRITVEEALAHPYLEQYYDPTDEPVAEEPFTFAMELDDLPKERL
KELIFQETARFQPGVLEAP
|
| Drugs and Mode of Action |
| Drug(s) |
BVD-523 |
Drug Info |
Phase 1/2 |
Cancer |
[1] |
|---|
| GDC-0994 |
Drug Info |
Phase 1 |
Solid tumours |
[2] |
| VAN-10-4-eluting stent |
Drug Info |
Phase 1 |
Restenosis |
[3] |
| Inhibitor |
6-[(E)-2-(4-Fluoro-phenyl)-vinyl]-9H-purine |
Drug Info |
[4] |
|---|
| VAN-10-4-eluting stent |
Drug Info |
[5] |
| Modulator |
BVD-523 |
Drug Info |
|
|---|
| GDC-0994 |
Drug Info |
|
| Pathways |
|
KEGG Pathway
|
MAPK signaling pathway
|
|
ErbB signaling pathway
|
|
Ras signaling pathway
|
|
Rap1 signaling pathway
|
|
cGMP-PKG signaling pathway
|
|
cAMP signaling pathway
|
|
Chemokine signaling pathway
|
|
HIF-1 signaling pathway
|
|
FoxO signaling pathway
|
|
Sphingolipid signaling pathway
|
|
Oocyte meiosis
|
|
mTOR signaling pathway
|
|
PI3K-Akt signaling pathway
|
|
Adrenergic signaling in cardiomyocytes
|
|
Vascular smooth muscle contraction
|
|
Dorso-ventral axis formation
|
|
TGF-beta signaling pathway
|
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Axon guidance
|
|
VEGF signaling pathway
|
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Osteoclast differentiation
|
|
Focal adhesion
|
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Adherens junction
|
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Gap junction
|
|
Signaling pathways regulating pluripotency of stem cells
|
|
Platelet activation
|
|
Toll-like receptor signaling pathway
|
|
NOD-like receptor signaling pathway
|
|
Natural killer cell mediated cytotoxicity
|
|
T cell receptor signaling pathway
|
|
B cell receptor signaling pathway
|
|
Fc epsilon RI signaling pathway
|
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Fc gamma R-mediated phagocytosis
|
|
TNF signaling pathway
|
|
Circadian entrainment
|
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Long-term potentiation
|
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Neurotrophin signaling pathway
|
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Retrograde endocannabinoid signaling
|
|
Glutamatergic synapse
|
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Cholinergic synapse
|
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Serotonergic synapse
|
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Long-term depression
|
|
Regulation of actin cytoskeleton
|
|
Insulin signaling pathway
|
|
GnRH signaling pathway
|
|
Progesterone-mediated oocyte maturation
|
|
Estrogen signaling pathway
|
|
Melanogenesis
|
|
Prolactin signaling pathway
|
|
Thyroid hormone signaling pathway
|
|
Oxytocin signaling pathway
|
|
Type II diabetes mellitus
|
|
Aldosterone-regulated sodium reabsorption
|
|
Alzheimer'
|
|
s disease
|
|
Prion diseases
|
|
Alcoholism
|
|
Shigellosis
|
|
Salmonella infection
|
|
Pertussis
|
|
Leishmaniasis
|
|
Chagas disease (American trypanosomiasis)
|
|
Toxoplasmosis
|
|
Tuberculosis
|
|
Hepatitis C
|
|
Hepatitis B
|
|
Influenza A
|
|
Pathways in cancer
|
|
Viral carcinogenesis
|
|
Proteoglycans in cancer
|
|
Colorectal cancer
|
|
Renal cell carcinoma
|
|
Pancreatic cancer
|
|
Endometrial cancer
|
|
Glioma
|
|
Prostate cancer
|
|
Thyroid cancer
|
|
Melanoma
|
|
Bladder cancer
|
|
Chronic myeloid leukemia
|
|
Acute myeloid leukemia
|
|
Non-small cell lung cancer
|
|
Central carbon metabolism in cancer
|
|
Choline metabolism in cancer
|
|
NetPath Pathway
|
IL5 Signaling Pathway
|
|
TCR Signaling Pathway
|
|
PANTHER Pathway
|
Alzheimer disease-amyloid secretase pathway
|
|
Angiogenesis
|
|
Apoptosis signaling pathway
|
|
B cell activation
|
|
EGF receptor signaling pathway
|
|
Endothelin signaling pathway
|
|
FGF signaling pathway
|
|
Inflammation mediated by chemokine and cytokine signaling pathway
|
|
Insulin/IGF pathway-mitogen activated protein kinase kinase/MAP kinase cascade
|
|
Integrin signalling pathway
|
|
Interferon-gamma signaling pathway
|
|
Interleukin signaling pathway
|
|
PDGF signaling pathway
|
|
Parkinson disease
|
|
TGF-beta signaling pathway
|
|
T cell activation
|
|
Toll receptor signaling pathway
|
|
VEGF signaling pathway
|
|
Ras Pathway
|
|
Angiotensin II-stimulated signaling through G proteins and beta-arrestin
|
|
CCKR signaling map ST
|
|
Pathway Interaction Database
|
Fc-epsilon receptor I signaling in mast cells
|
|
Endothelins
|
|
BCR signaling pathway
|
|
Signaling events mediated by PRL
|
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ErbB4 signaling events
|
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GMCSF-mediated signaling events
|
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Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met)
|
|
S1P3 pathway
|
|
EPHB forward signaling
|
|
Osteopontin-mediated events
|
|
S1P4 pathway
|
|
Presenilin action in Notch and Wnt signaling
|
|
TRAIL signaling pathway
|
|
CDC42 signaling events
|
|
Signaling events regulated by Ret tyrosine kinase
|
|
Angiopoietin receptor Tie2-mediated signaling
|
|
S1P1 pathway
|
|
Regulation of Telomerase
|
|
Netrin-mediated signaling events
|
|
Role of Calcineurin-dependent NFAT signaling in lymphocytes
|
|
Glucocorticoid receptor regulatory network
|
|
Arf6 downstream pathway
|
|
mTOR signaling pathway
|
|
IL2-mediated signaling events
|
|
EGF receptor (ErbB1) signaling pathway
|
|
Ras signaling in the CD4+ TCR pathway
|
|
Ceramide signaling pathway
|
|
Integrins in angiogenesis
|
|
IFN-gamma pathway
|
|
ErbB1 downstream signaling
|
|
ATF-2 transcription factor network
|
|
ErbB2/ErbB3 signaling events
|
|
ALK1 signaling events
|
|
PDGFR-beta signaling pathway
|
|
Neurotrophic factor-mediated Trk receptor signaling
|
|
Syndecan-1-mediated signaling events
|
|
Retinoic acid receptors-mediated signaling
|
|
Nongenotropic Androgen signaling
|
|
CXCR3-mediated signaling events
|
|
VEGFR1 specific signals
|
|
Regulation of cytoplasmic and nuclear SMAD2/3 signaling
|
|
Signaling events mediated by Stem cell factor receptor (c-Kit)
|
|
Signaling events mediated by VEGFR1 and VEGFR2
|
|
Syndecan-2-mediated signaling events
|
|
Cellular roles of Anthrax toxin
|
|
S1P2 pathway
|
|
Trk receptor signaling mediated by the MAPK pathway
|
|
Downstream signaling in na&
|
|
#xef
|
|
ve CD8+ T cells
|
|
VEGFR3 signaling in lymphatic endothelium
|
|
Alpha-synuclein signaling
|
|
FGF signaling pathway
|
|
Reactome
|
MAPK3 (ERK1) activation
|
|
RAF-independent MAPK1/3 activation
|
|
ISG15 antiviral mechanism
|
|
ERK/MAPK targets
|
|
Regulation of actin dynamics for phagocytic cup formation
|
|
Oxidative Stress Induced Senescence
|
|
Senescence-Associated Secretory Phenotype (SASP)
|
|
Oncogene Induced Senescence
|
|
FCERI mediated MAPK activation
|
|
Regulation of HSF1-mediated heat shock response
|
|
NCAM signaling for neurite out-growth
|
|
Activation of the AP-1 family of transcription factors
|
|
Thrombin signalling through proteinase activated receptors (PARs)
|
|
Negative regulation of FGFR1 signaling
|
|
Negative regulation of FGFR2 signaling
|
|
Negative regulation of FGFR3 signaling
|
|
Negative regulation of FGFR4 signaling
|
|
RHO GTPases Activate WASPs and WAVEs
|
|
RAF/MAP kinase cascade
|
|
MAP2K and MAPK activation
|
|
Negative feedback regulation of MAPK pathway
|
|
Negative regulation of MAPK pathway
|
|
Signal attenuation
|
|
Advanced glycosylation endproduct receptor signaling
|
|
Gastrin-CREB signalling pathway via PKC and MAPK
|
|
Growth hormone receptor signaling
|
|
WikiPathways
|
Toll-like receptor signaling pathway
|
|
Serotonin Receptor 4/6/7 and NR3C Signaling
|
|
Serotonin Receptor 2 and ELK-SRF/GATA4 signaling
|
|
Serotonin HTR1 Group and FOS Pathway
|
|
TCR Signaling Pathway
|
|
Hypothetical Network for Drug Addiction
|
|
EPO Receptor Signaling
|
|
TGF Beta Signaling Pathway
|
|
Regulation of Actin Cytoskeleton
|
|
IL-2 Signaling Pathway
|
|
Insulin Signaling
|
|
MAPK Cascade
|
|
IL-4 Signaling Pathway
|
|
MAPK Signaling Pathway
|
|
IL-6 signaling pathway
|
|
Signaling of Hepatocyte Growth Factor Receptor
|
|
Kit receptor signaling pathway
|
|
TCA Cycle Nutrient Utilization and Invasiveness of Ovarian Cancer
|
|
IL-3 Signaling Pathway
|
|
Cardiac Hypertrophic Response
|
|
MAP kinase activation in TLR cascade
|
|
Fc epsilon receptor (FCERI) signaling
|
|
RAF/MAP kinase cascade
|
|
Structural Pathway of Interleukin 1 (IL-1)
|
|
Genes and (Common) Pathways Underlying Drug Addiction
|
|
Signal Transduction of S1P Receptor
|
|
PDGF Pathway
|
|
Alpha 6 Beta 4 signaling pathway
|
|
Spinal Cord Injury
|
|
BDNF signaling pathway
|
|
Integrated Pancreatic Cancer Pathway
|
|
Oncostatin M Signaling Pathway
|
|
Corticotropin-releasing hormone
|
|
Interleukin-11 Signaling Pathway
|
|
AGE/RAGE pathway
|
|
TNF alpha Signaling Pathway
|
|
Prostate Cancer
|
|
Signaling Pathways in Glioblastoma
|
|
TSLP Signaling Pathway
|
|
IL-9 Signaling Pathway
|
|
IL17 signaling pathway
|
|
Alzheimers Disease
|
|
IL-7 Signaling Pathway
|
|
TWEAK Signaling Pathway
|
|
FSH signaling pathway
|
|
Leptin signaling pathway
|
|
RANKL/RANK Signaling Pathway
|
|
IL-1 signaling pathway
|
|
Thrombin signalling through proteinase activated receptors (PARs)
|
|
Signaling by Insulin receptor
|
|
Signaling by FGFR
|
|
RNA Polymerase I, RNA Polymerase III, and Mitochondrial Transcription
|
|
L1CAM interactions
|
|
Advanced glycosylation endproduct receptor signaling
|
|
Apoptosis Modulation and Signaling
|
|
MicroRNAs in cardiomyocyte hypertrophy
|
|
Regulation of toll-like receptor signaling pathway
|
|
Osteopontin Signaling
|
|
IL-5 Signaling Pathway
|
| References |
| REF 1 | ClinicalTrials.gov (NCT01781429) Phase I Dose-Escalation, Safety, Pharmacokinetic and Pharmacodynamic Study of BVD-523 in Patients With Advanced Malignancies. U.S. National Institutes of Health. |
|---|
| REF 2 | ClinicalTrials.gov (NCT01875705) A Dose-Escalation Study of GDC-0994 in Patients With Locally Advanced or Metastatic Solid Tumors. U.S. National Institutes of Health. |
|---|
| REF 3 | Drug-Eluting Stent for High Risk Patients. University of Strathclyde Glasgow. 2015 |
|---|
| REF 4 | J Med Chem. 2005 Feb 10;48(3):710-22.Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors. |
|---|
| REF 5 | WO patent application no. 2013,1850,32, Nanotherapeutics for drug targeting. |
|---|
