Target Information
Target General Infomation | |||||
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Target ID |
T60405
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Former ID |
TTDC00310
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Target Name |
mRNA of RAF proto-oncogene serine/threonine-protein kinase
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Gene Name |
RAF1
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Synonyms |
C-RAF; CRaf; Raf kinase; Raf-1; RAF1
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Target Type |
Clinical Trial
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Disease | Autoimmune diabetes [ICD10: E08-E13] | ||||
Cancer [ICD9: 140-229; ICD10: C00-C96] | |||||
Diabetic macular edema; Diabetic retinopathy [ICD9: 250, 250.5, 362.0-362.2, 362.01, 362.07, 362.53, 782.3; ICD10: E08-E13, E08.3, E09.3, E10.3, E11.3, E13.3, H35-H35.2, H35.8, H36] | |||||
Melanoma [ICD9: 172; ICD10: C43] | |||||
Parkinson's disease [ICD9: 332; ICD10: G20] | |||||
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48] | |||||
Function |
Serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade, and this critical regulatory link functions as a switch determining cell fate decisions including proliferation, differentiation, apoptosis, survival and oncogenic transformation. RAF1 activation initiates a mitogen-activated protein kinase (MAPK) cascade that comprises a sequential phosphorylation of the dual-specific MAPK kinases (MAP2K1/MEK1 and MAP2K2/MEK2) and the extracellular signal-regulated kinases (MAPK3/ERK1 and MAPK1/ERK2). The phosphorylated form of RAF1 (on residues Ser-338 and Ser-339, by PAK1) phosphorylates BAD/Bcl2- antagonist of cell death at 'Ser-75'. Phosphorylates adenylyl cyclases: ADCY2, ADCY5 and ADCY6, resulting in their activation. PhosphorylatesPPP1R12A resulting in inhibition of the phosphatase activity. Phosphorylates TNNT2/cardiac muscle troponin T. Can promote NF-kB activation and inhibit signal transducers involved in motility (ROCK2),apoptosis (MAP3K5/ASK1 and STK3/MST2), proliferation and angiogenesis (RB1). Can protect cells from apoptosis also by translocating to the mitochondria where it binds BCL2 and displaces BAD/Bcl2-antagonist of cell death. Regulates Rho signaling and migration, and is required for normal wound healing. Plays a role in the oncogenic transformation of epithelial cells via repression of the TJ protein, occludin (OCLN) by inducing the up-regulation of a transcriptional repressor SNAI2/SLUG, which induces down-regulation of OCLN. Restricts caspase activation in response to selected stimuli, notably Fas stimulation, pathogen-mediated macrophage apoptosis, and erythroid differentiation.
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BioChemical Class |
Target of antisense drug
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Target Validation |
T60405
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UniProt ID | |||||
EC Number |
EC 2.7.11.1
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Sequence |
MEHIQGAWKTISNGFGFKDAVFDGSSCISPTIVQQFGYQRRASDDGKLTDPSKTSNTIRV
FLPNKQRTVVNVRNGMSLHDCLMKALKVRGLQPECCAVFRLLHEHKGKKARLDWNTDAAS LIGEELQVDFLDHVPLTTHNFARKTFLKLAFCDICQKFLLNGFRCQTCGYKFHEHCSTKV PTMCVDWSNIRQLLLFPNSTIGDSGVPALPSLTMRRMRESVSRMPVSSQHRYSTPHAFTF NTSSPSSEGSLSQRQRSTSTPNVHMVSTTLPVDSRMIEDAIRSHSESASPSALSSSPNNL SPTGWSQPKTPVPAQRERAPVSGTQEKNKIRPRGQRDSSYYWEIEASEVMLSTRIGSGSF GTVYKGKWHGDVAVKILKVVDPTPEQFQAFRNEVAVLRKTRHVNILLFMGYMTKDNLAIV TQWCEGSSLYKHLHVQETKFQMFQLIDIARQTAQGMDYLHAKNIIHRDMKSNNIFLHEGL TVKIGDFGLATVKSRWSGSQQVEQPTGSVLWMAPEVIRMQDNNPFSFQSDVYSYGIVLYE LMTGELPYSHINNRDQIIFMVGRGYASPDLSKLYKNCPKAMKRLVADCVKKVKEERPLFP QILSSIELLQHSLPKINRSASEPSLHRAAHTEDINACTLTTSPRLPVF |
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Drugs and Mode of Action | |||||
Inhibitor | 5-(4-hydroxy-2,6-dimethylstyryl)nicotinic acid | Drug Info | [528356] | ||
6-Benzylsulfanyl-9H-purine | Drug Info | [527421] | |||
6-[(E)-2-(4-Fluoro-phenyl)-vinyl]-9H-purine | Drug Info | [527421] | |||
BIIB-024 | Drug Info | [543571] | |||
DEBROMOHYMENIALDISINE | Drug Info | [526243] | |||
GW-5074 | Drug Info | [526991] | |||
L-790070 | Drug Info | [529561] | |||
MLN2480 | Drug Info | [550478] | |||
PLX-ORI3 | Drug Info | [543571] | |||
SPN-803 | Drug Info | [543571] | |||
ZM-336372 | Drug Info | [529039] | |||
Modulator | RG7304 | Drug Info | [551608] | ||
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM) | |||||
TEP | EXP Info | ||||
Pathways | |||||
BioCyc Pathway | MAP kinase cascade | ||||
KEGG Pathway | MAPK signaling pathway | ||||
ErbB signaling pathway | |||||
Ras signaling pathway | |||||
Rap1 signaling pathway | |||||
cGMP-PKG signaling pathway | |||||
cAMP signaling pathway | |||||
Chemokine signaling pathway | |||||
FoxO signaling pathway | |||||
Sphingolipid signaling pathway | |||||
PI3K-Akt signaling pathway | |||||
Vascular smooth muscle contraction | |||||
VEGF signaling pathway | |||||
Focal adhesion | |||||
Gap junction | |||||
Signaling pathways regulating pluripotency of stem cells | |||||
Natural killer cell mediated cytotoxicity | |||||
T cell receptor signaling pathway | |||||
B cell receptor signaling pathway | |||||
Fc epsilon RI signaling pathway | |||||
Fc gamma R-mediated phagocytosis | |||||
Long-term potentiation | |||||
Neurotrophin signaling pathway | |||||
Serotonergic synapse | |||||
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 | |||||
Alcoholism | |||||
Tuberculosis | |||||
Hepatitis C | |||||
Hepatitis B | |||||
Influenza A | |||||
Pathways in cancer | |||||
Proteoglycans in cancer | |||||
MicroRNAs in cancer | |||||
Colorectal cancer | |||||
Renal cell carcinoma | |||||
Pancreatic cancer | |||||
Endometrial cancer | |||||
Glioma | |||||
Prostate 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 | ||||
IL2 Signaling Pathway | |||||
EGFR1 Signaling Pathway | |||||
PANTHER Pathway | Angiogenesis | ||||
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 | |||||
Interleukin signaling pathway | |||||
PDGF signaling pathway | |||||
T cell activation | |||||
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 | |||||
GMCSF-mediated signaling events | |||||
Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met) | |||||
CDC42 signaling events | |||||
SHP2 signaling | |||||
mTOR signaling pathway | |||||
IL2-mediated signaling events | |||||
IGF1 pathway | |||||
Ras signaling in the CD4+ TCR pathway | |||||
Ceramide signaling pathway | |||||
ErbB1 downstream signaling | |||||
ErbB2/ErbB3 signaling events | |||||
PDGFR-beta signaling pathway | |||||
p38 signaling mediated by MAPKAP kinases | |||||
Nongenotropic Androgen signaling | |||||
Internalization of ErbB1 | |||||
CXCR3-mediated signaling events | |||||
Signaling events mediated by Stem cell factor receptor (c-Kit) | |||||
Signaling events mediated by VEGFR1 and VEGFR2 | |||||
Class I PI3K signaling events mediated by Akt | |||||
Trk receptor signaling mediated by the MAPK pathway | |||||
Downstream signaling in na& | |||||
#xef | |||||
ve CD8+ T cells | |||||
Regulation of retinoblastoma protein | |||||
Signaling events mediated by focal adhesion kinase | |||||
PathWhiz Pathway | Fc Epsilon Receptor I Signaling in Mast Cells | ||||
Insulin Signalling | |||||
Reactome | Stimuli-sensing channels | ||||
GP1b-IX-V activation signalling | |||||
CREB phosphorylation through the activation of Ras | |||||
CD209 (DC-SIGN) signaling | |||||
RAF activation | |||||
MAP2K and MAPK activation | |||||
Negative feedback regulation of MAPK pathway | |||||
Negative regulation of MAPK pathway | |||||
WikiPathways | Serotonin Receptor 2 and ELK-SRF/GATA4 signaling | ||||
TCR Signaling Pathway | |||||
Senescence and Autophagy in Cancer | |||||
EPO Receptor Signaling | |||||
Regulation of Actin Cytoskeleton | |||||
IL-2 Signaling Pathway | |||||
Insulin Signaling | |||||
EGF/EGFR Signaling Pathway | |||||
MAPK Cascade | |||||
MAPK Signaling Pathway | |||||
TGF beta Signaling Pathway | |||||
Signaling of Hepatocyte Growth Factor Receptor | |||||
Kit receptor signaling pathway | |||||
Extracellular vesicle-mediated signaling in recipient cells | |||||
IL-3 Signaling Pathway | |||||
Cardiac Hypertrophic Response | |||||
Neurotransmitter Receptor Binding And Downstream Transmission In The Postsynaptic Cell | |||||
RAF/MAP kinase cascade | |||||
Iron uptake and transport | |||||
Nanoparticle-mediated activation of receptor signaling | |||||
PDGF Pathway | |||||
Retinoblastoma (RB) in Cancer | |||||
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 | |||||
B Cell Receptor Signaling Pathway | |||||
Prostate Cancer | |||||
Signaling Pathways in Glioblastoma | |||||
Endothelin Pathways | |||||
TWEAK Signaling Pathway | |||||
FSH signaling pathway | |||||
Leptin signaling pathway | |||||
Rap1 signalling | |||||
Integrin-mediated Cell Adhesion | |||||
GP1b-IX-V activation signalling | |||||
MicroRNAs in cardiomyocyte hypertrophy | |||||
IL-5 Signaling Pathway | |||||
References | |||||
Ref 521624 | ClinicalTrials.gov (NCT00100672) Study to Determine the Maximum Tolerated Dose of LErafAON in Patients With Advanced Cancer. U.S. National Institutes of Health. | ||||
Ref 523603 | ClinicalTrials.gov (NCT01425008) Study of MLN2480 in Patients With Relapsed or Refractory Solid Tumors Followed by a Dose Expansion in Patients With Metastatic Melanoma. U.S. National Institutes of Health. | ||||
Ref 527280 | Delivery of a liposomal c-raf-1 antisense oligonucleotide by weekly bolus dosing in patients with advanced solid tumors: a phase I study. Clin Cancer Res. 2004 Nov 1;10(21):7244-51. | ||||
Ref 548872 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800029757) | ||||
Ref 526243 | J Med Chem. 2002 Jan 17;45(2):529-32.Aldisine alkaloids from the Philippine sponge Stylissa massa are potent inhibitors of mitogen-activated protein kinase kinase-1 (MEK-1). | ||||
Ref 526991 | Bioorg Med Chem Lett. 2004 Feb 23;14(4):953-7.Discovery and in vitro evaluation of potent TrkA kinase inhibitors: oxindole and aza-oxindoles. | ||||
Ref 526998 | Combination with liposome-entrapped, ends-modified raf antisense oligonucleotide (LErafAON) improves the anti-tumor efficacies of cisplatin, epirubicin, mitoxantrone, docetaxel and gemcitabine. Anticancer Drugs. 2004 Mar;15(3):243-53. | ||||
Ref 527421 | J Med Chem. 2005 Feb 10;48(3):710-22.Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors. | ||||
Ref 528356 | Bioorg Med Chem Lett. 2006 Oct 15;16(20):5378-83. Epub 2006 Aug 4.Aza-stilbenes as potent and selective c-RAF inhibitors. | ||||
Ref 529039 | Biochem J. 2007 Dec 15;408(3):297-315.The selectivity of protein kinase inhibitors: a further update. | ||||
Ref 529561 | J Med Chem. 2008 Jul 24;51(14):4122-49. Epub 2008 Jun 26.Design, synthesis, and biological evaluation of novel Tri- and tetrasubstituted imidazoles as highly potent and specific ATP-mimetic inhibitors of p38 MAP kinase: focus on optimized interactions with the enzyme's surface-exposed front region. | ||||
Ref 543571 | (http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2184). | ||||
Ref 549605 | US patent application no. 5,952,229, Antisense oligonucleotide modulation of raf gene expression. | ||||
Ref 551023 | Design and development of antisense drugs. Expert Opin. Drug Discov. 2008 3(10):1189-1207. | ||||
Ref 551051 | Clinical pipeline report, company report or official report of ISIS Pharmaceuticals (2011). |
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