RAF1

Official Full Name

Raf-1 proto-oncogene, serine/threonine kinase

Organism

Homo sapiens

GeneID

5894

Background

This gene is the cellular homolog of viral raf gene (v-raf). The encoded protein is a MAP kinase kinase kinase (MAP3K), which functions downstream of the Ras family of membrane associated GTPases to which it binds directly. Once activated, the cellular RAF1 protein can phosphorylate to activate the dual specificity protein kinases MEK1 and MEK2, which in turn phosphorylate to activate the serine/threonine specific protein kinases, ERK1 and ERK2. Activated ERKs are pleiotropic effectors of cell physiology and play an important role in the control of gene expression involved in the cell division cycle, apoptosis, cell differentiation and cell migration. Mutations in this gene are associated with Noonan syndrome 5 and LEOPARD syndrome 2. [provided by RefSeq, Jul 2008]

Synonyms

NS5; CRAF; Raf-1; c-Raf; CMD1NN;

Bio Chemical Class

Kinase

Protein Sequence

MEHIQGAWKTISNGFGFKDAVFDGSSCISPTIVQQFGYQRRASDDGKLTDPSKTSNTIRVFLPNKQRTVVNVRNGMSLHDCLMKALKVRGLQPECCAVFRLLHEHKGKKARLDWNTDAASLIGEELQVDFLDHVPLTTHNFARKTFLKLAFCDICQKFLLNGFRCQTCGYKFHEHCSTKVPTMCVDWSNIRQLLLFPNSTIGDSGVPALPSLTMRRMRESVSRMPVSSQHRYSTPHAFTFNTSSPSSEGSLSQRQRSTSTPNVHMVSTTLPVDSRMIEDAIRSHSESASPSALSSSPNNLSPTGWSQPKTPVPAQRERAPVSGTQEKNKIRPRGQRDSSYYWEIEASEVMLSTRIGSGSFGTVYKGKWHGDVAVKILKVVDPTPEQFQAFRNEVAVLRKTRHVNILLFMGYMTKDNLAIVTQWCEGSSLYKHLHVQETKFQMFQLIDIARQTAQGMDYLHAKNIIHRDMKSNNIFLHEGLTVKIGDFGLATVKSRWSGSQQVEQPTGSVLWMAPEVIRMQDNNPFSFQSDVYSYGIVLYELMTGELPYSHINNRDQIIFMVGRGYASPDLSKLYKNCPKAMKRLVADCVKKVKEERPLFPQILSSIELLQHSLPKINRSASEPSLHRAAHTEDINACTLTTSPRLPVF

Open

Disease

Diabetes mellitus, Indeterminate colitis, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

10 +

Discontinued Drug

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Detailed Information

The RAF1 gene, originally designated c-Raf, is located on human chromosome 3p25.2 and encodes a serine/threonine protein kinase of approximately 74 kDa. As one of the three members of the RAF kinase family, together with ARAF and BRAF, RAF1 contains three conserved regions: CR1, CR2, and CR3. The CR1 region includes a RAS-binding domain (RBD) and a cysteine-rich domain (CRD), mediating interaction with activated RAS-GTP and membrane localization; the CR2 region is serine-rich and serves as a regulatory segment; CR3 contains the kinase catalytic core. RAF1 activity is tightly regulated through multiple mechanisms. Under basal conditions, RAF1 is maintained in an autoinhibited conformation through phosphorylation at S259 and S621 and binding to 14-3-3 proteins. Upon RAS-GTP binding to the RBD, RAF1 undergoes a conformational change, leading to S259 dephosphorylation, dissociation from 14-3-3 proteins, and translocation to the plasma membrane. RAF1 then achieves full activation via dimerization with other RAF family members, phosphorylating downstream substrates MEK1/2 and activating ERK1/2 to propagate the RAS-RAF-MEK-ERK cascade.

Figure 1. Regulation of RAF signaling by accessory proteins, illustrating how anchoring, adapter, docking, and scaffold proteins coordinate MAPK pathway activity and how RKIP inhibits RAF-mediated oncogenic signaling. (Bahar ME, et al., 2023)

RAF1 shares functional redundancy with other RAF members, particularly BRAF, but also exhibits distinct roles. While its kinase activity is lower than that of BRAF, RAF1 broadly influences cellular processes, including proliferation, apoptosis inhibition, metabolism, and migration. For instance, RAF1 phosphorylates BAD at S75 to inhibit pro-apoptotic activity, modulates mitochondrial energy metabolism through VDAC1 phosphorylation, and suppresses ROCK2 activity to affect cytoskeletal dynamics and cell motility. This multifunctionality positions RAF1 as a central node linking RAS signaling to diverse cellular physiological processes.

Pathogenic roles in developmental disorders and tumorigenesis

RAF1 variants contribute to both developmental abnormalities and cancer. Copy number duplication encompassing RAF1 can cause congenital heart defects such as Tetralogy of Fallot, often accompanied by severe limb malformations, due to gene dosage effects and hyperactivation of RAS-MAPK signaling. Gain-of-function point mutations in RAF1, such as S259L and L613V, are major causes of Noonan syndrome and LEOPARD syndrome, where disruption of autoinhibitory conformation leads to constitutive activation. Mutation site-specific effects vary: S259 mutations interfere with 14-3-3 binding to enhance kinase activity, whereas L613V promotes dimerization-driven activation.

In tumorigenesis, RAF1 variants primarily drive abnormal MAPK pathway activation. In non-small cell lung cancer (NSCLC), high RAF1 expression promotes resistance to the multi-kinase inhibitor anlotinib by suppressing apoptosis. Mechanistically, RAF1 overexpression upregulates anti-apoptotic Bcl-2 while downregulating pro-apoptotic Bax, impairing apoptotic signaling. RAF1 mutations also hold clinical relevance in rare sarcomas. A patient with advanced myxofibrosarcoma harboring RAF1 S259P achieved complete radiologic and molecular remission after treatment with the MEK inhibitor trametinib combined with the CDK4/6 inhibitor palbociclib. Functional analysis indicated that the S259P mutation disrupts RAF1 autoinhibition by preventing S259 phosphorylation and 14-3-3 interaction, markedly elevating ERK phosphorylation. Coexisting homozygous CDKN2A/B deletion suggested functional cooperation between RAF1 and cell cycle gene alterations.

Precision therapeutic strategies targeting aberrant RAF1

Therapeutic approaches for RAF1-mutant tumors focus on abnormal MAPK pathway activation. Preclinical studies show that MEK and ERK inhibitors exert strong antitumor effects in cells with activating RAF1 variants. The clinical success of trametinib combined with palbociclib in a patient with RAF1 S259P mutation demonstrates the feasibility of precision therapy guided by comprehensive genomic analysis and functional evidence, consistent with Molecular Tumor Board strategies. Overcoming RAF1-mediated resistance remains an important goal. In NSCLC, high RAF1 expression confers anlotinib resistance by blocking apoptosis, and combination therapy with BCL-2 inhibitors such as venetoclax has shown synergistic effects in preclinical models. Direct RAF1-targeting strategies are also under development, including second-generation RAF inhibitors like LY3009120 that inhibit both monomeric and dimeric RAF1 in various mutant models.

Challenges in RAF1 inhibitor development include structural similarity with other RAF members, particularly BRAF, and widespread expression in normal tissues, posing potential toxicity. Novel allosteric inhibitors focus on RAF1-specific pockets, such as sites near the DFG motif, while conformation-specific antibodies targeting mutations like S259P are being developed to selectively inhibit mutant protein without affecting wild-type function. PROTAC-based approaches to degrade mutant RAF1 have shown efficacy in preclinical leukemia models. These strategies collectively provide a foundation for targeted and precise interventions against RAF1-driven malignancies.

Reference

Drosten M, Barbacid M. Targeting the MAPK Pathway in KRAS-Driven Tumors. Cancer Cell. 2020 Apr 13;37(4):543-550.
Bahar ME, Kim HJ, Kim DR. Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies. Signal Transduct Target Ther. 2023 Dec 18;8(1):455.

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