RAF1 (v-raf-1 murine leukemia viral oncogene homolog 1)
2007-03-01 Max Cayo , David Yu Greentblatt , Muthusamy Kunnimalaiyaan , Herbert Chen AffiliationEndocrine Surgery Research Laboratories, Department of Surgery, Paul P. Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, Wisconsin, USA
Identity
HGNC
LOCATION
3p25.2
LOCUSID
ALIAS
CMD1NN,CRAF,NS5,Raf-1,c-Raf
FUSION GENES
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.).
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.
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.
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).
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.
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.
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.
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.
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.
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.
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
Oncogenesis
RAF-1 is typically over-expressed in thymic lymphomas from TCR transgenic mice.
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 17179102 | 2006 | Raf kinase inhibitor protein expression in a survival analysis of colorectal cancer patients. | Al-Mulla F et al |
| 11741918 | 2002 | Critical contribution of linker proteins to Raf kinase activation. | Anselmo AN et al |
| 7559496 | 1995 | The mouse B-raf gene encodes multiple protein isoforms with tissue-specific expression. | Barnier JV et al |
| 10758165 | 2000 | Raf induces NF-kappaB by membrane shuttle kinase MEKK1, a signaling pathway critical for transformation. | Baumann B et al |
| 3029685 | 1987 | The complete coding sequence of the human A-raf-1 oncogene and transforming activity of a human A-raf carrying retrovirus. | Beck TW et al |
| 2993863 | 1985 | Structure and biological activity of human homologs of the raf/mil oncogene. | Bonner TI et al |
| 9925253 | 1998 | Paclitaxel is preferentially cytotoxic to human cervical tumor cells with low Raf-1 kinase activity: implications for paclitaxel-based chemoradiation regimens. | Britten RA et al |
| 11427728 | 2001 | Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK-ERK independent mechanism. | Chen J et al |
| 12631622 | 2003 | Raf-1 and Bcl-2 induce distinct and common pathways that contribute to breast cancer drug resistance. | Davis JM et al |
| 9427625 | 1998 | Murine Ksr interacts with MEK and inhibits Ras-induced transformation. | Denouel-Galy A et al |
| 16175585 | 2006 | Metastasis suppressor gene Raf kinase inhibitor protein (RKIP) is a novel prognostic marker in prostate cancer. | Fu Z et al |
| 12813171 | 2003 | Effects of raf kinase inhibitor protein expression on suppression of prostate cancer metastasis. | Fu Z et al |
| 7744247 | 1995 | Raf1 interaction with Cdc25 phosphatase ties mitogenic signal transduction to cell cycle activation. | Galaktionov K et al |
| 16890795 | 2006 | Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway. | Gollob JA et al |
| 15930308 | 2005 | Pharmacologic inhibition of RAF-->MEK-->ERK signaling elicits pancreatic cancer cell cycle arrest through induced expression of p27Kip1. | Gysin S et al |
| 11296227 | 2001 | MEK kinase activity is not necessary for Raf-1 function. | Hüser M et al |
| 16243812 | 2005 | Reduction of Raf-1 kinase inhibitor protein expression correlates with breast cancer metastasis. | Hagan S et al |
| 12728271 | 2003 | Ras proteins: different signals from different locations. | Hancock JF et al |
| 16131330 | 2005 | Physiology and pathophysiology of type 3 deiodinase in humans. | Huang SA et al |
| 3520560 | 1986 | Actively transcribed genes in the raf oncogene group, located on the X chromosome in mouse and human. | Huebner K et al |
| 16603190 | 2006 | ZM336372, a Raf-1 activator, inhibits growth of pheochromocytoma cells. | Kappes A et al |
| 15151133 | 2004 | Raf kinase inhibitor protein: a prostate cancer metastasis suppressor gene. | Keller ET et al |
| 10634643 | 2000 | Overexpression 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 |
| 15305334 | 2004 | Prosaptide 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 |
| 16428931 | 2006 | The Raf-1 pathway: a molecular target for treatment of select neuroendocrine tumors? | Kunnimalaiyaan M et al |
| 14597674 | 2003 | Human homologue of Drosophila CNK interacts with Ras effector proteins Raf and Rlf. | Lanigan TM et al |
| 15526167 | 2004 | Novel 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 |
| 12691824 | 2003 | Down-regulation of Raf-1 kinase is associated with paclitaxel resistance in human breast cancer MCF-7/Adr cells. | Lee M et al |
| 16945999 | 2006 | Transforming growth factor-beta1 sensitivity is altered in Abl-Myc- and Raf-Myc-induced mouse pre-B-cell tumors. | Letterio J et al |
| 10783161 | 2000 | The leucine-rich repeat protein SUR-8 enhances MAP kinase activation and forms a complex with Ras and Raf. | Li W et al |
| 17178882 | 2006 | Sorafenib 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 |
| 10768864 | 2000 | Expression of the A-raf proto-oncogene in the normal adult and embryonic mouse. | Luckett JC et al |
| 12087097 | 2002 | Inhibition of phosphorylation of BAD and Raf-1 by Akt sensitizes human ovarian cancer cells to paclitaxel. | Mabuchi S et al |
| 11742498 | 2001 | Association of c-Raf expression with survival and its targeting with antisense oligonucleotides in ovarian cancer. | McPhillips F et al |
| 15662129 | 2005 | Inhibition of gastric cancer angiogenesis by vector-based RNA interference for Raf-1. | Meng F et al |
| 11296228 | 2001 | Embryonic lethality and fetal liver apoptosis in mice lacking the c-raf-1 gene. | Mikula M et al |
| 17145707 | 2006 | Selection 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 |
| 11309192 | 2001 | KSR: a MAPK scaffold of the Ras pathway? | Morrison DK et al |
| 14570565 | 2003 | Regulation of MAP kinase signaling modules by scaffold proteins in mammals. | Morrison DK et al |
| 16184551 | 2006 | Comparison of strategies targeting Raf-1 mRNA in ovarian cancer. | Mullen P et al |
| 14673957 | 2004 | Activation of the Raf-1/MEK/Erk kinase pathway by a novel Cdc25 inhibitor in human prostate cancer cells. | Nemoto K et al |
| 15754006 | 2005 | Systemic 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 |
| 12213567 | 2002 | Fidelity and spatio-temporal control in MAP kinase (ERKs) signalling. | Pouysségur J et al |
| 9879662 | 1998 | Estrogen activates raf-1 kinase and induces expression of Egr-1 in MCF-7 breast cancer cells. | Pratt MA et al |
| 8805280 | 1996 | Post-natal lethality and neurological and gastrointestinal defects in mice with targeted disruption of the A-Raf protein kinase gene. | Pritchard CA et al |
| 10022606 | 1999 | Raf-1-induced cell cycle arrest in LNCaP human prostate cancer cells. | Ravi RK et al |
| 8036991 | 1994 | MAP kinases ERK1 and ERK2: pleiotropic enzymes in a ubiquitous signaling network. | Robbins DJ et al |
| 16951188 | 2006 | AAL881, a novel small molecule inhibitor of RAF and vascular endothelial growth factor receptor activities, blocks the growth of malignant glioma. | Sathornsumetee S et al |
| 11389083 | 2001 | High-throughput tissue microarray analysis of 3p25 (RAF1) and 8p12 (FGFR1) copy number alterations in urinary bladder cancer. | Simon R et al |
| 12851216 | 2003 | Raf-1 activation suppresses neuroendocrine marker and hormone levels in human gastrointestinal carcinoid cells. | Sippel RS et al |
| 16613992 | 2006 | Autocrine/paracrine regulation of breast cancer cell proliferation by growth hormone releasing hormone via Ras, Raf, and mitogen-activated protein kinase. | Siriwardana G et al |
| 1690378 | 1990 | Expression of raf family proto-oncogenes in normal mouse tissues. | Storm SM et al |
| 14555207 | 2003 | Raf and the road to cell survival: a tale of bad spells, ring bearers and detours. | Troppmair J et al |
| 11709560 | 2002 | 14-3-3 proteins: active cofactors in cellular regulation by serine/threonine phosphorylation. | Tzivion G et al |
| 16926634 | 2006 | In-vivo activation of Raf-1 inhibits tumor growth and development in a xenograft model of human medullary thyroid cancer. | Vaccaro A et al |
| 15956248 | 2005 | ZM336372, a Raf-1 activator, suppresses growth and neuroendocrine hormone levels in carcinoid tumor cells. | Van Gompel JJ et al |
| 8929532 | 1996 | Bcl-2 targets the protein kinase Raf-1 to mitochondria. | Wang HG et al |
| 8692945 | 1996 | Bcl-2 interacting protein, BAG-1, binds to and activates the kinase Raf-1. | Wang HG et al |
| 9819434 | 1998 | Raf-1 physically interacts with Rb and regulates its function: a link between mitogenic signaling and cell cycle regulation. | Wang S et al |
| 12432273 | 2002 | The 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 |
| 15520807 | 2004 | The RAF proteins take centre stage. | Wellbrock C et al |
| 9009833 | 1996 | How Ras-related proteins talk to their effectors. | Wittinghofer A et al |
| 9767153 | 1998 | Craf-1 protein kinase is essential for mouse development. | Wojnowski L et al |
| 10576742 | 1999 | Phosphorylation 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
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
PharmGKB
| Entity ID | Name | Type | Evidence | Association | PK | PD | PMIDs |
|---|---|---|---|---|---|---|---|
| PA134913435 | SHC3 | Gene | Pathway | associated | |||
| PA134971076 | SHC2 | Gene | Pathway | associated | |||
| PA26946 | CSK | Gene | Pathway | associated | 20124951 | ||
| PA284 | MAP2K7 | Gene | Pathway | associated | 20124951 | ||
| PA28962 | GRB2 | Gene | Pathway | associated | |||
| PA29444 | HRAS | Gene | Pathway | associated | 20124951, 28362716 | ||
| PA30196 | KRAS | Gene | Pathway | associated | 20124951, 28362716 | ||
| PA30584 | MAP2K1 | Gene | Pathway | associated | 20124951, 28362716 | ||
| PA30587 | MAP2K2 | Gene | Pathway | associated | 20124951, 28362716 | ||
| PA30588 | MAP2K3 | Gene | Pathway | associated | 20124951 | ||
| PA30589 | MAP2K4 | Gene | Pathway | associated | 20124951 | ||
| PA30590 | MAP2K5 | Gene | Pathway | associated | 20124951 | ||
| PA30591 | MAP2K6 | Gene | Pathway | associated | 20124951 | ||
| PA30932 | MRAS | Gene | Pathway | associated | |||
| PA31768 | NRAS | Gene | Pathway | associated | 20124951, 28362716 | ||
| PA33759 | PRKCA | Gene | Pathway | associated | 20124951 | ||
| PA33761 | PRKCB | Gene | Pathway | associated | 20124951 | ||
| PA33763 | PRKCD | Gene | Pathway | associated | 20124951 | ||
| PA33765 | PRKCE | Gene | Pathway | associated | 20124951 | ||
| PA33766 | PRKCG | Gene | Pathway | associated | 20124951 | ||
| PA33767 | PRKCH | Gene | Pathway | associated | 20124951 | ||
| PA33768 | PRKCI | Gene | Pathway | associated | 20124951 | ||
| PA33773 | PRKCQ | Gene | Pathway | associated | 20124951 | ||
| PA33775 | PRKCZ | Gene | Pathway | associated | 20124951 | ||
| PA34861 | RRAS | Gene | Pathway | associated | |||
| PA35746 | SHC1 | Gene | Pathway | associated | |||
| PA36024 | SOS1 | Gene | Pathway | associated | |||
| PA443622 | Carcinoma, Non-Small-Cell Lung | Disease | ClinicalAnnotation | associated | PD | 21636554 | |
| PA448803 | carboplatin | Chemical | ClinicalAnnotation | associated | PD | 21636554 | |
| PA449014 | cisplatin | Chemical | ClinicalAnnotation | associated | PD | 21636554 | |
| PA449383 | docetaxel | Chemical | ClinicalAnnotation | associated | PD | 21636554 | |
| PA449748 | gemcitabine | Chemical | ClinicalAnnotation | associated | PD | 21636554 | |
| PA450761 | paclitaxel | Chemical | ClinicalAnnotation | associated | PD | 21636554 | |
| PA7000 | sorafenib | Chemical | Pathway | associated | 20124951, 28362716 |
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 37787490 | 2024 | RAF1 mutation leading to hypertrophic cardiomyopathy in a Chinese family with a history of sudden cardiac death: A diagnostic insight into Noonan syndrome. | 1 |
| 37940778 | 2024 | Cross-Talking Pathways of Rapidly Accelerated Fibrosarcoma-1 (RAF-1) in Alzheimer's Disease. | 0 |
| 38629245 | 2024 | RAF1 gene fusions are recurrent driver events in infantile fibrosarcoma-like mesenchymal tumors. | 0 |
| 37787490 | 2024 | RAF1 mutation leading to hypertrophic cardiomyopathy in a Chinese family with a history of sudden cardiac death: A diagnostic insight into Noonan syndrome. | 1 |
| 37940778 | 2024 | Cross-Talking Pathways of Rapidly Accelerated Fibrosarcoma-1 (RAF-1) in Alzheimer's Disease. | 0 |
| 38629245 | 2024 | RAF1 gene fusions are recurrent driver events in infantile fibrosarcoma-like mesenchymal tumors. | 0 |
| 35475426 | 2023 | Cardiac features of Noonan syndrome in Japanese patients. | 2 |
| 36244648 | 2023 | HDLBP Promotes Hepatocellular Carcinoma Proliferation and Sorafenib Resistance by Suppressing Trim71-dependent RAF1 Degradation. | 4 |
| 36564468 | 2023 | The sodium channel subunit SCNN1B suppresses colorectal cancer via suppression of active c-Raf and MAPK signaling cascade. | 4 |
| 36927384 | 2023 | Molecular analyses of the C-terminal CRAF variants associated with cardiomyopathy reveal their opposing impacts on the active conformation of the kinase domain. | 1 |
| 37020037 | 2023 | RAF1 contributes to cell proliferation and STAT3 activation in colorectal cancer independently of microsatellite and KRAS status. | 4 |
| 37066513 | 2023 | RAF1 deficiency causes a lethal syndrome that underscores RTK signaling during embryogenesis. | 3 |
| 37170083 | 2023 | SHOC2 mediates the drug-resistance of triple-negative breast cancer cells to everolimus. | 0 |
| 37258577 | 2023 | TRIM22 promotes the proliferation of glioblastoma cells by activating MAPK signaling and accelerating the degradation of Raf-1. | 4 |
| 37344639 | 2023 | Molecular 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
