General Information of Drug Therapeutic Target (DTT) (ID: TTB18GJ)

DTT Name Proto-oncogene c-RAF (c-RAF)
Synonyms cRaf; Raf-1; RAF proto-oncogene serine/threonine-protein kinase; RAF
Gene Name RAF1
DTT Type
Clinical trial target
[1]
BioChemical Class
Kinase
UniProt ID
RAF1_HUMAN
TTD ID
T23673
3D Structure
Download
2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
EC Number
EC 2.7.11.1
Sequence
MEHIQGAWKTISNGFGFKDAVFDGSSCISPTIVQQFGYQRRASDDGKLTDPSKTSNTIRV
FLPNKQRTVVNVRNGMSLHDCLMKALKVRGLQPECCAVFRLLHEHKGKKARLDWNTDAAS
LIGEELQVDFLDHVPLTTHNFARKTFLKLAFCDICQKFLLNGFRCQTCGYKFHEHCSTKV
PTMCVDWSNIRQLLLFPNSTIGDSGVPALPSLTMRRMRESVSRMPVSSQHRYSTPHAFTF
NTSSPSSEGSLSQRQRSTSTPNVHMVSTTLPVDSRMIEDAIRSHSESASPSALSSSPNNL
SPTGWSQPKTPVPAQRERAPVSGTQEKNKIRPRGQRDSSYYWEIEASEVMLSTRIGSGSF
GTVYKGKWHGDVAVKILKVVDPTPEQFQAFRNEVAVLRKTRHVNILLFMGYMTKDNLAIV
TQWCEGSSLYKHLHVQETKFQMFQLIDIARQTAQGMDYLHAKNIIHRDMKSNNIFLHEGL
TVKIGDFGLATVKSRWSGSQQVEQPTGSVLWMAPEVIRMQDNNPFSFQSDVYSYGIVLYE
LMTGELPYSHINNRDQIIFMVGRGYASPDLSKLYKNCPKAMKRLVADCVKKVKEERPLFP
QILSSIELLQHSLPKINRSASEPSLHRAAHTEDINACTLTTSPRLPVF
Function
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. Phosphorylates PPP1R12A 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. 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.
KEGG Pathway
EGFR tyrosine kinase inhibitor resistance (hsa01521 )
Endocrine resistance (hsa01522 )
MAPK signaling pathway (hsa04010 )
ErbB signaling pathway (hsa04012 )
Ras signaling pathway (hsa04014 )
Rap1 signaling pathway (hsa04015 )
cGMP-PKG signaling pathway (hsa04022 )
cAMP signaling pathway (hsa04024 )
Chemokine signaling pathway (hsa04062 )
FoxO signaling pathway (hsa04068 )
Sphingolipid signaling pathway (hsa04071 )
Phospholipase D signaling pathway (hsa04072 )
Autophagy - animal (hsa04140 )
mTOR signaling pathway (hsa04150 )
PI3K-Akt signaling pathway (hsa04151 )
Apoptosis (hsa04210 )
Cellular senescence (hsa04218 )
Vascular smooth muscle contraction (hsa04270 )
Axon guidance (hsa04360 )
VEGF signaling pathway (hsa04370 )
Apelin signaling pathway (hsa04371 )
Focal adhesion (hsa04510 )
Gap junction (hsa04540 )
Signaling pathways regulating pluripotency of stem cells (hsa04550 )
Neutrophil extracellular trap formation (hsa04613 )
C-type lectin receptor signaling pathway (hsa04625 )
JAK-STAT signaling pathway (hsa04630 )
Natural killer cell mediated cytotoxicity (hsa04650 )
T cell receptor signaling pathway (hsa04660 )
B cell receptor signaling pathway (hsa04662 )
Fc epsilon RI signaling pathway (hsa04664 )
Fc gamma R-mediated phagocytosis (hsa04666 )
Long-term potentiation (hsa04720 )
Neurotrophin signaling pathway (hsa04722 )
Serotonergic synapse (hsa04726 )
Long-term depression (hsa04730 )
Regulation of actin cytoskeleton (hsa04810 )
Insulin signaling pathway (hsa04910 )
GnRH signaling pathway (hsa04912 )
Progesterone-mediated oocyte maturation (hsa04914 )
Estrogen signaling pathway (hsa04915 )
Melanogenesis (hsa04916 )
Prolactin signaling pathway (hsa04917 )
Thyroid hormone signaling pathway (hsa04919 )
Oxytocin signaling pathway (hsa04921 )
Relaxin signaling pathway (hsa04926 )
Parathyroid hormone synthesis, secretion and action (hsa04928 )
GnRH secretion (hsa04929 )
Growth hormone synthesis, secretion and action (hsa04935 )
Alzheimer disease (hsa05010 )
Pathways of neurodegeneration - multiple diseases (hsa05022 )
Alcoholism (hsa05034 )
Salmonella infection (hsa05132 )
Tuberculosis (hsa05152 )
Hepatitis C (hsa05160 )
Hepatitis B (hsa05161 )
Human cytomegalovirus infection (hsa05163 )
Influenza A (hsa05164 )
Human papillomavirus infection (hsa05165 )
Kaposi sarcoma-associated herpesvirus infection (hsa05167 )
Human immunodeficiency virus 1 infection (hsa05170 )
Pathways in cancer (hsa05200 )
Proteoglycans in cancer (hsa05205 )
MicroRNAs in cancer (hsa05206 )
Chemical carcinogenesis - receptor activation (hsa05207 )
Chemical carcinogenesis - reactive oxygen species (hsa05208 )
Colorectal cancer (hsa05210 )
Renal cell carcinoma (hsa05211 )
Pancreatic cancer (hsa05212 )
Endometrial cancer (hsa05213 )
Glioma (hsa05214 )
Prostate cancer (hsa05215 )
Melanoma (hsa05218 )
Bladder cancer (hsa05219 )
Chronic myeloid leukemia (hsa05220 )
Acute myeloid leukemia (hsa05221 )
Non-small cell lung cancer (hsa05223 )
Breast cancer (hsa05224 )
Hepatocellular carcinoma (hsa05225 )
Gastric cancer (hsa05226 )
Central carbon metabolism in cancer (hsa05230 )
Choline metabolism in cancer (hsa05231 )
PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235 )
Reactome Pathway
Rap1 signalling (R-HSA-392517 )
GP1b-IX-V activation signalling (R-HSA-430116 )
CD209 (DC-SIGN) signaling (R-HSA-5621575 )
RAF activation (R-HSA-5673000 )
MAP2K and MAPK activation (R-HSA-5674135 )
Negative feedback regulation of MAPK pathway (R-HSA-5674499 )
Negative regulation of MAPK pathway (R-HSA-5675221 )
Signaling by moderate kinase activity BRAF mutants (R-HSA-6802946 )
Signaling by high-kinase activity BRAF mutants (R-HSA-6802948 )
Signaling by BRAF and RAF1 fusions (R-HSA-6802952 )
Paradoxical activation of RAF signaling by kinase inactive BRAF (R-HSA-6802955 )
Signaling downstream of RAS mutants (R-HSA-9649948 )
Signaling by RAF1 mutants (R-HSA-9656223 )
SHOC2 M1731 mutant abolishes MRAS complex function (R-HSA-9726840 )
Gain-of-function MRAS complexes activate RAF signaling (R-HSA-9726842 )
Stimuli-sensing channels (R-HSA-2672351 )

Molecular Interaction Atlas (MIA) of This DTT

Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DTT
4 Clinical Trial Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
BGB-3245 DM1X3L0 Solid tumour/cancer 2A00-2F9Z Phase 2 [2]
Semapimod DMIJNLG Autoimmune diabetes 5A10 Phase 2 [1]
Belvarafenib DM0ZNAR Solid tumour/cancer 2A00-2F9Z Phase 1 [3]
GDC-5573 DMJA27W Solid tumour/cancer 2A00-2F9Z Phase 1 [4]
------------------------------------------------------------------------------------

Molecular Expression Atlas (MEA) of This DTT

Molecular Expression Atlas (MEA) Jump to Detail Molecular Expression Atlas of This DTT
Disease Name ICD 11 Studied Tissue p-value Fold-Change Z-score
Rectal cancer 2C82 Rectal colon tissue 2.11E-03 0.21 1.51
Myelodysplastic syndrome 2C82 Bone marrow 1.64E-02 -0.18 -0.58
Breast cancer 2C82 Breast tissue 7.45E-09 0.21 0.56
Acute myelocytic leukaemia 2C82 Bone marrow 3.16E-14 -0.35 -0.57
Head and neck cancer 2C82 Head and neck tissue 2.35E-29 -0.37 -1.8
------------------------------------------------------------------------------------

References

1 Specific inhibition of c-Raf activity by semapimod induces clinical remission in severe Crohn's disease. J Immunol. 2005 Aug 15;175(4):2293-300.
2 Clinical pipeline report, company report or official report of BeiGene.
3 Clinical pipeline report, company report or official report of Hanmi Pharmaceutical.
4 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)