RAF1 (v-raf-1 murine leukemia viral oncogene homolog 1)

2007-03-01   Max Cayo  , David Yu Greentblatt  , Muthusamy Kunnimalaiyaan  , Herbert Chen  

Endocrine Surgery Research Laboratories, Department of Surgery, Paul P. Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, Wisconsin, USA

Identity

HGNC
RAF1
LOCATION
3p25.2
LOCUSID
5894
ALIAS
CMD1NN,CRAF,NS5,Raf-1,c-Raf
FUSION GENES
Show Gene Fusions

DNA/RNA

Note

History and Nomenclature:
c-Raf-1 was the first successfully cloned functional human homolog of the v-Raf gene, and thus the gene product of c-Raf-1 has historically been referred to in the literature simply as Raf-1. Subsequently, B-Raf and A-Raf-1 paralogues ( BRAF, located in Xq13 and ARAF, located in Xp11) were discovered. A suitable nomenclature is as follows: A-RAF, B-RAF, and C-RAF for the functional human proteins and A-RAF, B-RAF, and C-RAF for the corresponding genes; a-raf, b-raf, and c-raf for the murine proteins and A-Raf, B-Raf, and C-Raf for the corresponding genes. Raf-1 (or RAF-1) is generally taken to mean C-RAF-1 but could apply to A-RAF-1 equally. Here, RAF-1 will be taken to mean C-RAF-1 (RAF-1 = C-RAF-1, etc.).

Description

C-RAF (RAF-1, C-RAF-1) encompasses 80,570 bp of DNA; 17 Exons.

Transcription

RAF-1 transcribed mRNA contains 3212-3216 nucleotides.

Proteins

Description

The RAF proteins share three conserved domains: two (CR1 and CR2) in the N terminus and a third (CR3-encoding for the serine/threonine kinase domain) in the C terminus. The RAF proteins exhibit complex regulation involving numerous phosphorylation sites throughout the proteins. Despite constitutional similarity, the Raf isoforms have been shown to carry out non-redundant functions, implying that they are distinct.
RAF-1 (C-RAF-1): 72-74 kDa.
Note: A-RAF: about 68 kDa.
Note: B-RAF (which undergoes alternate splicing): ranges from 75 to 100 kDa.

Expression

C-RAF (RAF-1) and A-RAF mRNA is expressed ubiquitously. A-RAF mRNA is highly expressed in urogenital organs. B-RAF is expressed in a wide range of tissues, but most substantially in neuronal tissues.

Localisation

Cytosolic.

Function

RAF proteins are part of the conserved MAPK (mitogen-activated protein kinase)/ERK (extracellular signal-regulated kinase) signaling cascade between the cell surface and the nucleus. RAF is regulated by the upstream RAS family of small G proteins. RAS is predominantly located on the inner leaflet of the plasma membrane and is functionally activated by GTP-binding. Binding of various extracellular ligands such as growth factors and hormones activates RAS and subsequently RAF proteins. RAS binds directly to the N-terminal regulatory domain or RAF (the RAS binding domain (RBD)). RAS interacts secondarily with the cysteine-rich domain (CRD) on CR1 of RAF. RAS-RAF binding can be affected by 14-3-3 proteins and other scaffold/adaptor proteins kinase suppressor of RAS (KSR), the multidomain protein connector-enhancer of KSR (CNK), and the leucine-rich-repeat protein suppressor of RAS mutations-8 (SUR8), which cause formation of various homo- and heterodimers and subsequently affect signal transduction. RAF activation leads to activation of the protein kinases MEK1 and MEK2 and subsequently the MAPK proteins ERK1 and ERK2. The downstream effects of MEK1/2-ERK1/2 activation are varied, complex, and depend on the cellular context. Resultant effects include activation of transcription factors involved in tumorigenesis, cell growth, survival, differentiation, metabolism, and cytoskeletal rearrangements. RAF-1 (C-RAF-1), A-RAF, and B-RAF are all capable of activating the MEK1/2-ERK1/2 signaling pathway.
RAF-1 is capable of activating the NF-kB transcription factor through an unknown mechanism that does not seem to involve direct phosphorylation of NF-kB and is independent of MEK1/2-ERK1/2 signaling.
RAF-1 is known to directly affect cell survival through phosphorylation of BAG1 (BCL2-associated athanogene-1), an anti-apoptotic protein that binds to BCL2, a second anti-apoptotic factor, also the prototype for a family of mammalian genes involved in mitochondrial outer membrane permeability (MOMP), thus restoring its function. BCL2 also targets RAF-1 to the mitochondrial membrane, where it is able to more readily phosphorylate substrates. The RAF-1/BAG1/BCL2 interaction allows RAF-1 to phosphorylate the pro-apoptotic protein BAD at the mitochondrial membrane, promoting cell survival.
Other known substrates of RAF-1 include the phosphatase CDC25C, the apoptosis signal-regulating kinase-1 (ASK1), and the tumor-suppressor protein retinoblastoma (Rb).
RAF-1 is tightly regulated by the AKT/PKB pathway through phosphorylation at S259.

Mutations

Somatic

It has been widely established that RAF-1 over activity, typically via ras-activating mutations, is central to tumorigenesis and cell proliferation in numerous cancers (about 30% of all human cancers). However, it has come to the fore that oncogenesis may be due to ras/RAF-1 dysregulation (either increased or decreased expression) rather than increases in ras/RAF-1 activity exclusively.

Implicated in

Entity name
Medullary Thyroid Cancer (MTC)
Disease
A neuroendocrine tumor derived from parafollicular C cells of the thyroid gland, MTC is the third most common form of thyroid cancer, accounting for 3-5% of all cases. MTC cells secrete hormones and tumor markers such as calcitonin, chromogranin A (CgA), and carcinoembryonic antigen (CEA).
Symptoms are related to either direct invasion or metastasis (neck mass, dyspnea, dysphagia, voice changes, pain) or tumor secretion of bioactive amines and peptides (diarrhea, flushing).
Prognosis
Currently, surgery is the only potentially curative therapy for patients with MTC. The recommended operation is total thyroidectomy with lymph node dissection. However, 50% of patients treated with surgery suffer persistent or recurrent disease.
Oncogenesis
20% of patients with medullary thyroid cancer have an autosomal dominant inherited form of the disease, which is the result of well-characterized point mutations in the RET proto-oncogene. RAF-1 is conserved but not expressed at baseline in MTC. Pre-clinical studies have shown that activation of RAF-1 in MTC (TT) cells by means of RAF-1 gene transfection or RAF-1 activating small molecules (ZM336372) results in tumor cell growth inhibition in vitro and in vivo.
Entity name
Carcinoid Tumors
Disease
Carcinoids are tumors that arise from the diffuse neuroendocrine cell system of the gut, lungs, and other organs. The incidence is 1-5 per 100,000 individuals. Carcinoids frequently metastasize to the liver and are the second most common source of isolated liver metastases. Carcinoids secrete various bioactive hormones such as 5-HT (5-hydroxy tryptophan, also known as serotonin) and chromogranin A.
Prognosis
Patients with hepatic metastases suffer debilitating symptoms such as abdominal pain, flushing, bronchoconstriction, and diarrhea. Palliative treatment for these hormone-induced symptoms includes somatostatin analogs (such as octeotride). Conventional anticancer treatments such as chemotherapy and external beam radiation is largely ineffective for carcinoid tumors.
Oncogenesis
RAF-1 activation is detrimental to tumorigenesis in carcinoid cells. Marked reduction in neuroendocrine phenotypic markers such as human achaete-scute complex like-1 (ASCL-1) and bioactive hormones 5-HT, chromogranin A, and synaptophysin has been noted upon RAF-1 activation using an estrogen-inducible RAF-1 construct in human GI (BON) and pulmonary carcinoid cell lines (NCI-H727) .
Treatment of GI carcinoid cells with RAF-1 activator ZM336372 led to a decrease in bioactive hormone levels, a suppression of cellular proliferation, an increase in cell cycle inhibitors p21 and p18, as well as a decrease in the neuroendocrine phenotypic marker ASCL-1. ZM336372 treatments also led to progressive phosphorylation (activation) of MEK1/2, ERK1/2, and RAF-1.
Entity name
Small Cell Lung Cancer (SCLC)
Disease
SCLC tends to present with metastatic and regional spread. Carcinoids rarely metastasize, arise from major bronchi, and express neuron-specific enolase, chromogranin, and synaptophysin. Neuroendocrine carcinoids or atypical carcinoids have a more aggressive course.
Oncogenesis
Human small-cell lung cancer (SCLC) cell lines rarely harbor ras-activating mutations. In one cell line of SCLC, DMS53, it was shown that by RAF-1 induction using an estrogen-inducible RAF-1 construct SCLC cells underwent differentiation and G1-specific growth arrest in conjunction with MEK/ERK1/2 pathway activation.
Entity name
Non-Small Cell Lung Cancer (NSCLC).
Disease
Adenocarcinoma is the most common type of NSCLC accounting for about 40% of cases. Lesions are generally located peripherally and develop systemic metastases despite small primary tumors. 25% of NSCLC are squamous cell carcinomas which often remain localized.
Oncogenesis
RAF-1 is over-expressed due to oncogenic ras mutations in about 35% of NSCLC.
The majority of NSCLC exhibits EGFR over-expression leading to upregulation of RAF-1 activity. NSCLC has been shown to be mediated by a TGF-a/EGFR-mediated autocrine loop activated by signaling involving RAF-1 and PI3K-Akt.
Entity name
Pheochromocytoma.
Disease
Pheochromocytomas are neuroectodermal in origin and arise from the chromaffin cells of the adrenal medulla. 10% of tumors are bilateral. Typical symptoms such as hypertension, headaches, diaphoresis, palpitations, diarrhea, and skin rashes, are related to tumor production of catecholamines, especially in patients with metastases. Pheochromocytoma is potentially fatal, but relatively uncommon (2-8 cases per million people annually). Curative therapy is surgery, usually accomplished by laparoscopic adrenalectomy.
Oncogenesis
Activation of MEK1/2-ERK1/2 is necessary for differentiation of pheochromocytoma (PC12) cells and leads to decreased cell proliferation. RAF-1 activation in pheochromocytoma cells using ZM336372 led to cellular differentiation, growth arrest, and a decrease in the neuroendocrine marker chromogranin A.
Entity name
Non-Neuroendocrine Cancers with ras-activating Mutations.
Oncogenesis
About 30% of all human cancers express ras-activating mutations. More than 85% of pancreatic adenocarcinomas, and 50% of colonic adenocarcinomas harbor K-ras mutations. K-ras is an upstream effector of RAF-1 in the RAF-1/MEK/ERK1/2 signaling pathway. Ras mutations have also been linked to tumorigenesis of cholangiocarcinoma, adenocarcinoma of the lung, squamous cell cancer, gastric adenocarcinoma, small bowel adenocarcinoma, and malignant melanoma.
Entity name
Colorectal Cancer.
Oncogenesis
RAF-1 is over-activated due to oncogenic ras mutations in about 50% of colon cancers. These mutations are associated with poor prognosis, and are necessary for maintenance of the malignant phenotype.
RAF-1 inhibition in response to interaction with RAF kinase inhibitor protein (RKIP) (up-regulated in conjunction with the nuclear factor kappa B signaling pathway) has been linked with overall and disease-free survival in patients with colorectal cancers. RKIP has been identified as potentially useful for identifying early-stage CRC patients at risk for relapse.
Entity name
Pancreatic Carcinoma.
Oncogenesis
RAF-1 is overactivated due to oncogenic ras mutations in about 90% of pancreatic carcinomas (Panc-1 and Mia-PaCa2). It has been shown that malignancy of these cells is reduced using k-ras RNAi. Pharmacological inhibition of the RAF/MEK/ERK pathway in pancreatic cancer cell lines (via MEK inhibition) results in reduction in cellular proliferation and an increase in cell cycle arrest.
Entity name
Hepatocellular Carcinoma (HCC)
Oncogenesis
RAF-1 is over-activated in about 50% of biopsies while the RAF-1 protein is over-expressed in nearly 100% of all HCCs. Angiogenesis and other functions essential to tumorigenesis in HCC have been reported to depend on the RAF/MEK/ERK signaling pathway. RAF-1 inhibitor Sorafenib has been reported (in-vitro and in-vivo) to inhibit RAF-1 activity, leading to decreased MEK/ERK activity, reduced cellular proliferation, and apoptosis in several HCC cell lines including HepG2 and PLC/PRF/5.
Entity name
Prostate Cancer.
Oncogenesis
RAF kinase inhibitor protein (RKIP) coding mRNAs have been observed to activate interferon-inducible 2,5-oligoadenylate synthetases (OAS). OAS activity is characteristically increased (via these mRNAs) in prostate cancer cell lines PC3, LNCaP and DU145. RKIP expression is detectable in primary prostate cancer sections but not in metastases. This suggests RKIPs characterization as an anti-metastasis gene using the RAF/MEK/ERK signaling pathway is appropriate.
RAF-1 inhibition using systemically delivered novel cationic cardiolipin liposomes (NeoPhectin-AT) containing a small interfering RNA (siRNA) against RAF-1 causes tumor growth inhibition in a xenograft model of human prostate cancer.
RAF/MEK/ERK signaling pathway activation via a biologically active peptide called a prosaptide (TX14A) stimulates cell proliferation/survival, migration, and invasion in human prostate cancer cells.
NSC 95397 and NSC 672121, cdc25 inhibitors, were shown to activate the RAF/MEK/ERK pathway in prostate cancer cells.
RAF-1 activation in LNCaP prostate cancer cells using an estrogen-inducible construct led to growth inhibition.
Entity name
Breast Cancer.
Oncogenesis
Growth hormone releasing hormone (GHRH) has been shown to regulate breast cancer cell proliferation and differentiation. In MDA-231 breast cancer cells, exogenous GHRH stimulated dose-dependent proliferation. RAF-1 inhibition using the agent PD98059 caused prevention of MAPK phosphorylation by GHRH as well as reduced cellular proliferation.
Proliferative effects of steroid hormone estradiol on MCF-7 breast cancer cells have been linked with increased expression of RAF-1, possibly due to direct activation of RAF-1 by estradiol.
RAF kinase inhibitor protein (RKIP) is associated with metastasis suppression. RKIP expression is lost in lymph node metastases. This suggests RKIP is a metastasis inhibitor gene and that RAF-1 expression enables metastasis.
The PTK inhibitor AG 879 inhibits proliferation of human breast cancer cells through inhibition of MAP kinase activation through inhibition of expression of the RAF-1 gene.
RAF-1 down-regulation is associated with paclitaxel drug resistance in human breast cancer cell line MCF-7/Adr.
Entity name
Renal Cell Carcinoma.
Oncogenesis
RAF-1 is overactivated in conjunction with loss of function of the VHL ( von Hippel-Lindau) tumor-suppressor gene.
Entity name
Glioma .
Oncogenesis
RAF-1 inhibitor AAL881 inhibited growth of glioma cell xenografts.
Entity name
Cervical Cancer.
Oncogenesis
Low RAF-1 kinase activity is significantly associated with paclitaxel sensitivity in cervical cancers.
Entity name
Ovarian Cancer.
Oncogenesis
RAF-1 dysregulation is associated with poor prognosis and possibly carcinogenesis. RAF-1 inhibition using RNAi reduces cellular proliferatin and inhibits ovarian tumor cell growth in vitro and in vivo. Similar results were observed using antisense oligonucleotide (ASO) therapy (ISIS 5132 and ISIS 13650).
RAF-1 inhibition by the Akt pathway sensitizes human ovarian cancer cells to the drug paclitaxel.
Entity name
Gastric Cancer.
Oncogenesis
RAF-1 inactivation using RNAi in gastric cancer cell line SGC7901 led to dramatic reductions in angiogenesis, increased apoptosis, and decreased cellular proliferation.
Entity name
Bladder Cancer.
Oncogenesis
RAF-1 gene amplification was detected in 4% of bladder cancer samples. Deletions at the RAF-1 locus were detected in 2.2% of these samples. Both amplifications and deletions were heavily correlated with high tumor grade (P < 0.00001), advanced stage (P < 0.0001), and poor survival (P
Entity name
Lymphoma.
Oncogenesis
RAF-1 is typically over-expressed in thymic lymphomas from TCR transgenic mice.

Article Bibliography

Pubmed IDLast YearTitleAuthors
171791022006Raf kinase inhibitor protein expression in a survival analysis of colorectal cancer patients.Al-Mulla F et al
117419182002Critical contribution of linker proteins to Raf kinase activation.Anselmo AN et al
75594961995The mouse B-raf gene encodes multiple protein isoforms with tissue-specific expression.Barnier JV et al
107581652000Raf induces NF-kappaB by membrane shuttle kinase MEKK1, a signaling pathway critical for transformation.Baumann B et al
30296851987The complete coding sequence of the human A-raf-1 oncogene and transforming activity of a human A-raf carrying retrovirus.Beck TW et al
29938631985Structure and biological activity of human homologs of the raf/mil oncogene.Bonner TI et al
99252531998Paclitaxel is preferentially cytotoxic to human cervical tumor cells with low Raf-1 kinase activity: implications for paclitaxel-based chemoradiation regimens.Britten RA et al
114277282001Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK-ERK independent mechanism.Chen J et al
126316222003Raf-1 and Bcl-2 induce distinct and common pathways that contribute to breast cancer drug resistance.Davis JM et al
94276251998Murine Ksr interacts with MEK and inhibits Ras-induced transformation.Denouel-Galy A et al
161755852006Metastasis suppressor gene Raf kinase inhibitor protein (RKIP) is a novel prognostic marker in prostate cancer.Fu Z et al
128131712003Effects of raf kinase inhibitor protein expression on suppression of prostate cancer metastasis.Fu Z et al
77442471995Raf1 interaction with Cdc25 phosphatase ties mitogenic signal transduction to cell cycle activation.Galaktionov K et al
168907952006Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway.Gollob JA et al
159303082005Pharmacologic inhibition of RAF-->MEK-->ERK signaling elicits pancreatic cancer cell cycle arrest through induced expression of p27Kip1.Gysin S et al
112962272001MEK kinase activity is not necessary for Raf-1 function.Hüser M et al
162438122005Reduction of Raf-1 kinase inhibitor protein expression correlates with breast cancer metastasis.Hagan S et al
127282712003Ras proteins: different signals from different locations.Hancock JF et al
161313302005Physiology and pathophysiology of type 3 deiodinase in humans.Huang SA et al
35205601986Actively transcribed genes in the raf oncogene group, located on the X chromosome in mouse and human.Huebner K et al
166031902006ZM336372, a Raf-1 activator, inhibits growth of pheochromocytoma cells.Kappes A et al
151511332004Raf kinase inhibitor protein: a prostate cancer metastasis suppressor gene.Keller ET et al
106346432000Overexpression of Ras, Raf and L-myc but not Bcl-2 family proteins is linked with resistance to TCR-mediated apoptosis and tumorigenesis in thymic lymphomas from TCR transgenic mice.Kobzdej M et al
153053342004Prosaptide TX14A stimulates growth, migration, and invasion and activates the Raf-MEK-ERK-RSK-Elk-1 signaling pathway in prostate cancer cells.Koochekpour S et al
164289312006The Raf-1 pathway: a molecular target for treatment of select neuroendocrine tumors?Kunnimalaiyaan M et al
145976742003Human homologue of Drosophila CNK interacts with Ras effector proteins Raf and Rlf.Lanigan TM et al
155261672004Novel actions of tyrphostin AG 879: inhibition of RAF-1 and HER-2 expression combined with strong antitumoral effects on breast cancer cells.Larsson LI et al
126918242003Down-regulation of Raf-1 kinase is associated with paclitaxel resistance in human breast cancer MCF-7/Adr cells.Lee M et al
169459992006Transforming growth factor-beta1 sensitivity is altered in Abl-Myc- and Raf-Myc-induced mouse pre-B-cell tumors.Letterio J et al
107831612000The leucine-rich repeat protein SUR-8 enhances MAP kinase activation and forms a complex with Ras and Raf.Li W et al
171788822006Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5.Liu L et al
107688642000Expression of the A-raf proto-oncogene in the normal adult and embryonic mouse.Luckett JC et al
120870972002Inhibition of phosphorylation of BAD and Raf-1 by Akt sensitizes human ovarian cancer cells to paclitaxel.Mabuchi S et al
117424982001Association of c-Raf expression with survival and its targeting with antisense oligonucleotides in ovarian cancer.McPhillips F et al
156621292005Inhibition of gastric cancer angiogenesis by vector-based RNA interference for Raf-1.Meng F et al
112962282001Embryonic lethality and fetal liver apoptosis in mice lacking the c-raf-1 gene.Mikula M et al
171457072006Selection and cloning of poly(rC)-binding protein 2 and Raf kinase inhibitor protein RNA activators of 2',5'-oligoadenylate synthetase from prostate cancer cells.Molinaro RJ et al
113091922001KSR: a MAPK scaffold of the Ras pathway?Morrison DK et al
145705652003Regulation of MAP kinase signaling modules by scaffold proteins in mammals.Morrison DK et al
161845512006Comparison of strategies targeting Raf-1 mRNA in ovarian cancer.Mullen P et al
146739572004Activation of the Raf-1/MEK/Erk kinase pathway by a novel Cdc25 inhibitor in human prostate cancer cells.Nemoto K et al
157540062005Systemic delivery of RafsiRNA using cationic cardiolipin liposomes silences Raf-1 expression and inhibits tumor growth in xenograft model of human prostate cancer.Pal A et al
122135672002Fidelity and spatio-temporal control in MAP kinase (ERKs) signalling.Pouysségur J et al
98796621998Estrogen activates raf-1 kinase and induces expression of Egr-1 in MCF-7 breast cancer cells.Pratt MA et al
88052801996Post-natal lethality and neurological and gastrointestinal defects in mice with targeted disruption of the A-Raf protein kinase gene.Pritchard CA et al
100226061999Raf-1-induced cell cycle arrest in LNCaP human prostate cancer cells.Ravi RK et al
80369911994MAP kinases ERK1 and ERK2: pleiotropic enzymes in a ubiquitous signaling network.Robbins DJ et al
169511882006AAL881, a novel small molecule inhibitor of RAF and vascular endothelial growth factor receptor activities, blocks the growth of malignant glioma.Sathornsumetee S et al
113890832001High-throughput tissue microarray analysis of 3p25 (RAF1) and 8p12 (FGFR1) copy number alterations in urinary bladder cancer.Simon R et al
128512162003Raf-1 activation suppresses neuroendocrine marker and hormone levels in human gastrointestinal carcinoid cells.Sippel RS et al
166139922006Autocrine/paracrine regulation of breast cancer cell proliferation by growth hormone releasing hormone via Ras, Raf, and mitogen-activated protein kinase.Siriwardana G et al
16903781990Expression of raf family proto-oncogenes in normal mouse tissues.Storm SM et al
145552072003Raf and the road to cell survival: a tale of bad spells, ring bearers and detours.Troppmair J et al
11709560200214-3-3 proteins: active cofactors in cellular regulation by serine/threonine phosphorylation.Tzivion G et al
169266342006In-vivo activation of Raf-1 inhibits tumor growth and development in a xenograft model of human medullary thyroid cancer.Vaccaro A et al
159562482005ZM336372, a Raf-1 activator, suppresses growth and neuroendocrine hormone levels in carcinoid tumor cells.Van Gompel JJ et al
89295321996Bcl-2 targets the protein kinase Raf-1 to mitochondria.Wang HG et al
86929451996Bcl-2 interacting protein, BAG-1, binds to and activates the kinase Raf-1.Wang HG et al
98194341998Raf-1 physically interacts with Rb and regulates its function: a link between mitogenic signaling and cell cycle regulation.Wang S et al
124322732002The effects of beta-estradiol on Raf activity, cell cycle progression and growth factor synthesis in the MCF-7 breast cancer cell line.Weinstein-Oppenheimer CR et al
155208072004The RAF proteins take centre stage.Wellbrock C et al
90098331996How Ras-related proteins talk to their effectors.Wittinghofer A et al
97671531998Craf-1 protein kinase is essential for mouse development.Wojnowski L et al
105767421999Phosphorylation and regulation of Raf by Akt (protein kinase B).Zimmermann S et al

Other Information

Locus ID:

NCBI: 5894
MIM: 164760
HGNC: 9829
Ensembl: ENSG00000132155

Variants:

dbSNP: 5894
ClinVar: 5894
TCGA: ENSG00000132155
COSMIC: RAF1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000132155ENST00000251849P04049
ENSG00000132155ENST00000251849L7RRS6
ENSG00000132155ENST00000416093A0A0B4J1W9
ENSG00000132155ENST00000423275A0A0B4J1W9
ENSG00000132155ENST00000432427H7C155
ENSG00000132155ENST00000442415P04049
ENSG00000132155ENST00000442415A0A0S2Z559

Expression (GTEx)

0
50
100
150
200
Adipose - Subcutaneous
Adipose - Visceral
Adrenal Gland
Artery - Aorta
Artery - Tibial
Bladder
Brain - Amygdala
Brain - Anterior cingulate cortex
Brain - Caudate
Brain - Cerebellar Hemisphere
Brain - Cerebellum
Brain - Cortex
Brain - Frontal Cortex
Brain - Hippocampus
Brain - Hypothalamus
Brain - Nucleus accumbens
Brain - Putamen
Brain - Spinal cord
Brain - Substantia nigra
Breast - Mammary Tissue
Cells - Cultured fibroblasts
Cells - EBV - transformed lymphocytes
Cervix - Ectocervix
Cervix - Endocervix
Colon - Sigmoid
Colon - Transverse
Esophagus - Gastroesophageal Junction
Esophagus - Mucosa
Esophagus - Muscularis
Fallopian Tube
Heart - Atrial Appendage
Heart - Left Ventricle
Kidney - Cortex
Kidney - Medulla
Liver
Lung
Minor Salivary Gland
Muscle - Skeletal
Nerve - Tibial
Ovary
Pancreas
Pituitary
Prostate
Skin - Not Sun Exposed
Skin - Sun Exposed
Small Intestine - Terminal Ileum
Spleen
Stomach
Testis
Thyroid
Uterus
Vagina
Whole Blood

Pathways

PathwaySourceExternal ID
MAPK signaling pathwayKEGGko04010
ErbB signaling pathwayKEGGko04012
Autophagy - animalKEGGko04140
mTOR signaling pathwayKEGGko04150
ApoptosisKEGGko04210
Axon guidanceKEGGko04360
VEGF signaling pathwayKEGGko04370
Focal adhesionKEGGko04510
Gap junctionKEGGko04540
Jak-STAT signaling pathwayKEGGko04630
Natural killer cell mediated cytotoxicityKEGGko04650
T cell receptor signaling pathwayKEGGko04660
B cell receptor signaling pathwayKEGGko04662
Fc epsilon RI signaling pathwayKEGGko04664
Long-term potentiationKEGGko04720
Long-term depressionKEGGko04730
Regulation of actin cytoskeletonKEGGko04810
Insulin signaling pathwayKEGGko04910
GnRH signaling pathwayKEGGko04912
Progesterone-mediated oocyte maturationKEGGko04914
MelanogenesisKEGGko04916
Colorectal cancerKEGGko05210
Renal cell carcinomaKEGGko05211
Pancreatic cancerKEGGko05212
Endometrial cancerKEGGko05213
GliomaKEGGko05214
Prostate cancerKEGGko05215
MelanomaKEGGko05218
Bladder cancerKEGGko05219
Chronic myeloid leukemiaKEGGko05220
Acute myeloid leukemiaKEGGko05221
Non-small cell lung cancerKEGGko05223
MAPK signaling pathwayKEGGhsa04010
ErbB signaling pathwayKEGGhsa04012
Autophagy - animalKEGGhsa04140
mTOR signaling pathwayKEGGhsa04150
ApoptosisKEGGhsa04210
Axon guidanceKEGGhsa04360
VEGF signaling pathwayKEGGhsa04370
Focal adhesionKEGGhsa04510
Gap junctionKEGGhsa04540
Jak-STAT signaling pathwayKEGGhsa04630
Natural killer cell mediated cytotoxicityKEGGhsa04650
T cell receptor signaling pathwayKEGGhsa04660
B cell receptor signaling pathwayKEGGhsa04662
Fc epsilon RI signaling pathwayKEGGhsa04664
Long-term potentiationKEGGhsa04720
Long-term depressionKEGGhsa04730
Regulation of actin cytoskeletonKEGGhsa04810
Insulin signaling pathwayKEGGhsa04910
GnRH signaling pathwayKEGGhsa04912
MelanogenesisKEGGhsa04916
Pathways in cancerKEGGhsa05200
Colorectal cancerKEGGhsa05210
Renal cell carcinomaKEGGhsa05211
Pancreatic cancerKEGGhsa05212
Endometrial cancerKEGGhsa05213
GliomaKEGGhsa05214
Prostate cancerKEGGhsa05215
MelanomaKEGGhsa05218
Bladder cancerKEGGhsa05219
Chronic myeloid leukemiaKEGGhsa05220
Acute myeloid leukemiaKEGGhsa05221
Non-small cell lung cancerKEGGhsa05223
Vascular smooth muscle contractionKEGGhsa04270
Chemokine signaling pathwayKEGGko04062
Vascular smooth muscle contractionKEGGko04270
Chemokine signaling pathwayKEGGhsa04062
Neurotrophin signaling pathwayKEGGko04722
Neurotrophin signaling pathwayKEGGhsa04722
Fc gamma R-mediated phagocytosisKEGGko04666
Fc gamma R-mediated phagocytosisKEGGhsa04666
Progesterone-mediated oocyte maturationKEGGhsa04914
Hepatitis CKEGGko05160
Hepatitis CKEGGhsa05160
TuberculosisKEGGko05152
TuberculosisKEGGhsa05152
Influenza AKEGGko05164
Influenza AKEGGhsa05164
Serotonergic synapseKEGGhsa04726
AlcoholismKEGGhsa05034
AlcoholismKEGGko05034
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
Hepatitis BKEGGhsa05161
Proteoglycans in cancerKEGGhsa05205
Proteoglycans in cancerKEGGko05205
Estrogen signaling pathwayKEGGhsa04915
Estrogen signaling pathwayKEGGko04915
Prolactin signaling pathwayKEGGhsa04917
Prolactin signaling pathwayKEGGko04917
MicroRNAs in cancerKEGGhsa05206
MicroRNAs in cancerKEGGko05206
Ras signaling pathwayKEGGhsa04014
Rap1 signaling pathwayKEGGhsa04015
Rap1 signaling pathwayKEGGko04015
FoxO signaling pathwayKEGGhsa04068
Thyroid hormone signaling pathwayKEGGhsa04919
Oxytocin signaling pathwayKEGGhsa04921
Oxytocin signaling pathwayKEGGko04921
cGMP-PKG signaling pathwayKEGGhsa04022
cGMP-PKG signaling pathwayKEGGko04022
cAMP signaling pathwayKEGGhsa04024
cAMP signaling pathwayKEGGko04024
Signaling pathways regulating pluripotency of stem cellsKEGGhsa04550
Signaling pathways regulating pluripotency of stem cellsKEGGko04550
Central carbon metabolism in cancerKEGGhsa05230
Choline metabolism in cancerKEGGhsa05231
Central carbon metabolism in cancerKEGGko05230
Choline metabolism in cancerKEGGko05231
MAPK (ERK1/2) signalingKEGGhsa_M00687
MAPK (ERK1/2) signalingKEGGM00687
Sphingolipid signaling pathwayKEGGhsa04071
Sphingolipid signaling pathwayKEGGko04071
Neuronal SystemREACTOMER-HSA-112316
Transmission across Chemical SynapsesREACTOMER-HSA-112315
Neurotransmitter Receptor Binding And Downstream Transmission In The Postsynaptic CellREACTOMER-HSA-112314
Activation of NMDA receptor upon glutamate binding and postsynaptic eventsREACTOMER-HSA-442755
Post NMDA receptor activation eventsREACTOMER-HSA-438064
CREB phosphorylation through the activation of RasREACTOMER-HSA-442742
DiseaseREACTOMER-HSA-1643685
Diseases of signal transductionREACTOMER-HSA-5663202
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
Rap1 signallingREACTOMER-HSA-392517
Innate Immune SystemREACTOMER-HSA-168249
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491
RAF/MAP kinase cascadeREACTOMER-HSA-5673001
RAF activationREACTOMER-HSA-5673000
MAP2K and MAPK activationREACTOMER-HSA-5674135
Negative regulation of MAPK pathwayREACTOMER-HSA-5675221
Negative feedback regulation of MAPK pathwayREACTOMER-HSA-5674499
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
FCERI mediated MAPK activationREACTOMER-HSA-2871796
C-type lectin receptors (CLRs)REACTOMER-HSA-5621481
CD209 (DC-SIGN) signalingREACTOMER-HSA-5621575
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-2 signalingREACTOMER-HSA-451927
Interleukin receptor SHC signalingREACTOMER-HSA-912526
Interleukin-3, 5 and GM-CSF signalingREACTOMER-HSA-512988
HemostasisREACTOMER-HSA-109582
Platelet activation, signaling and aggregationREACTOMER-HSA-76002
GP1b-IX-V activation signallingREACTOMER-HSA-430116
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
GRB2 events in EGFR signalingREACTOMER-HSA-179812
SHC1 events in EGFR signalingREACTOMER-HSA-180336
Signaling by Insulin receptorREACTOMER-HSA-74752
Insulin receptor signalling cascadeREACTOMER-HSA-74751
IRS-mediated signallingREACTOMER-HSA-112399
SOS-mediated signallingREACTOMER-HSA-112412
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
Signalling to ERKsREACTOMER-HSA-187687
Signalling to RASREACTOMER-HSA-167044
Signalling to p38 via RIT and RINREACTOMER-HSA-187706
Prolonged ERK activation eventsREACTOMER-HSA-169893
Frs2-mediated activationREACTOMER-HSA-170968
ARMS-mediated activationREACTOMER-HSA-170984
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by VEGFREACTOMER-HSA-194138
VEGFA-VEGFR2 PathwayREACTOMER-HSA-4420097
VEGFR2 mediated cell proliferationREACTOMER-HSA-5218921
Signaling by SCF-KITREACTOMER-HSA-1433557
MAPK family signaling cascadesREACTOMER-HSA-5683057
MAPK1/MAPK3 signalingREACTOMER-HSA-5684996
Signaling by GPCRREACTOMER-HSA-372790
Gastrin-CREB signalling pathway via PKC and MAPKREACTOMER-HSA-881907
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)REACTOMER-HSA-2404192
IGF1R signaling cascadeREACTOMER-HSA-2428924
IRS-related events triggered by IGF1RREACTOMER-HSA-2428928
Signaling by LeptinREACTOMER-HSA-2586552
Transmembrane transport of small moleculesREACTOMER-HSA-382551
Ion channel transportREACTOMER-HSA-983712
Stimuli-sensing channelsREACTOMER-HSA-2672351
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
NCAM signaling for neurite out-growthREACTOMER-HSA-375165
Phospholipase D signaling pathwayKEGGko04072
Phospholipase D signaling pathwayKEGGhsa04072
EGFR tyrosine kinase inhibitor resistanceKEGGko01521
Endocrine resistanceKEGGko01522
EGFR tyrosine kinase inhibitor resistanceKEGGhsa01521
Endocrine resistanceKEGGhsa01522
RET signalingREACTOMER-HSA-8853659
Breast cancerKEGGko05224
Breast cancerKEGGhsa05224
Oncogenic MAPK signalingREACTOMER-HSA-6802957
Signaling by RAS mutantsREACTOMER-HSA-6802949
Signaling by high-kinase activity BRAF mutantsREACTOMER-HSA-6802948
Signaling by moderate kinase activity BRAF mutantsREACTOMER-HSA-6802946
Paradoxical activation of RAF signaling by kinase inactive BRAFREACTOMER-HSA-6802955
Signaling by BRAF and RAF fusionsREACTOMER-HSA-6802952
Apelin signaling pathwayKEGGhsa04371

Protein levels (Protein atlas)

Not detected
Low
Medium
High
cerebral cortex
cerebellum
hippocampus
caudate
thyroid gland
parathyroid gland
adrenal gland
nasopharynx
bronchus
lung
oral mucosa
salivary gland
esophagus
stomach 1
stomach 2
duodenum
small intestine
colon
rectum
liver
gallbladder
pancreas
kidney
urinary bladder
testis
epididymis
seminal vesicle
prostate
vagina
ovary
fallopian tube
endometrium 1
endometrium 2
cervix, uterine
placenta
breast
heart muscle
smooth muscle
skeletal muscle
soft tissue 1
soft tissue 2
adipose tissue
skin 1
skin 2
appendix
spleen
lymph node
tonsil
bone marrow

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA134913435SHC3GenePathwayassociated
PA134971076SHC2GenePathwayassociated
PA26946CSKGenePathwayassociated20124951
PA284MAP2K7GenePathwayassociated20124951
PA28962GRB2GenePathwayassociated
PA29444HRASGenePathwayassociated20124951, 28362716
PA30196KRASGenePathwayassociated20124951, 28362716
PA30584MAP2K1GenePathwayassociated20124951, 28362716
PA30587MAP2K2GenePathwayassociated20124951, 28362716
PA30588MAP2K3GenePathwayassociated20124951
PA30589MAP2K4GenePathwayassociated20124951
PA30590MAP2K5GenePathwayassociated20124951
PA30591MAP2K6GenePathwayassociated20124951
PA30932MRASGenePathwayassociated
PA31768NRASGenePathwayassociated20124951, 28362716
PA33759PRKCAGenePathwayassociated20124951
PA33761PRKCBGenePathwayassociated20124951
PA33763PRKCDGenePathwayassociated20124951
PA33765PRKCEGenePathwayassociated20124951
PA33766PRKCGGenePathwayassociated20124951
PA33767PRKCHGenePathwayassociated20124951
PA33768PRKCIGenePathwayassociated20124951
PA33773PRKCQGenePathwayassociated20124951
PA33775PRKCZGenePathwayassociated20124951
PA34861RRASGenePathwayassociated
PA35746SHC1GenePathwayassociated
PA36024SOS1GenePathwayassociated
PA443622Carcinoma, Non-Small-Cell LungDiseaseClinicalAnnotationassociatedPD21636554
PA448803carboplatinChemicalClinicalAnnotationassociatedPD21636554
PA449014cisplatinChemicalClinicalAnnotationassociatedPD21636554
PA449383docetaxelChemicalClinicalAnnotationassociatedPD21636554
PA449748gemcitabineChemicalClinicalAnnotationassociatedPD21636554
PA450761paclitaxelChemicalClinicalAnnotationassociatedPD21636554
PA7000sorafenibChemicalPathwayassociated20124951, 28362716

References

Pubmed IDYearTitleCitations
377874902024RAF1 mutation leading to hypertrophic cardiomyopathy in a Chinese family with a history of sudden cardiac death: A diagnostic insight into Noonan syndrome.1
379407782024Cross-Talking Pathways of Rapidly Accelerated Fibrosarcoma-1 (RAF-1) in Alzheimer's Disease.0
386292452024RAF1 gene fusions are recurrent driver events in infantile fibrosarcoma-like mesenchymal tumors.0
377874902024RAF1 mutation leading to hypertrophic cardiomyopathy in a Chinese family with a history of sudden cardiac death: A diagnostic insight into Noonan syndrome.1
379407782024Cross-Talking Pathways of Rapidly Accelerated Fibrosarcoma-1 (RAF-1) in Alzheimer's Disease.0
386292452024RAF1 gene fusions are recurrent driver events in infantile fibrosarcoma-like mesenchymal tumors.0
354754262023Cardiac features of Noonan syndrome in Japanese patients.2
362446482023HDLBP Promotes Hepatocellular Carcinoma Proliferation and Sorafenib Resistance by Suppressing Trim71-dependent RAF1 Degradation.4
365644682023The sodium channel subunit SCNN1B suppresses colorectal cancer via suppression of active c-Raf and MAPK signaling cascade.4
369273842023Molecular analyses of the C-terminal CRAF variants associated with cardiomyopathy reveal their opposing impacts on the active conformation of the kinase domain.1
370200372023RAF1 contributes to cell proliferation and STAT3 activation in colorectal cancer independently of microsatellite and KRAS status.4
370665132023RAF1 deficiency causes a lethal syndrome that underscores RTK signaling during embryogenesis.3
371700832023SHOC2 mediates the drug-resistance of triple-negative breast cancer cells to everolimus.0
372585772023TRIM22 promotes the proliferation of glioblastoma cells by activating MAPK signaling and accelerating the degradation of Raf-1.4
373446392023Molecular and cellular evidence for the impact of a hypertrophic cardiomyopathy-associated RAF1 variant on the structure and function of contractile machinery in bioartificial cardiac tissues.5

Citation

Max Cayo ; David Yu Greentblatt ; Muthusamy Kunnimalaiyaan ; Herbert Chen

RAF1 (v-raf-1 murine leukemia viral oncogene homolog 1)

Atlas Genet Cytogenet Oncol Haematol. 2007-03-01

Online version: http://atlasgeneticsoncology.org/gene/42032/gene-fusions/haematological-explorer/