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c-Raf

c-Raf, also known as RAF1 or Raf-1, is a serine/threonine-specific protein kinase encoded by the RAF1 proto-oncogene on human chromosome 3, serving as a critical mediator in the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) signaling cascade that regulates cellular processes such as proliferation, differentiation, survival, and apoptosis.^[1] Originally identified in the 1980s as the cellular homolog of the v-raf viral oncogene, c-Raf functions downstream of Ras GTPases, where binding to active Ras-GTP recruits it to the plasma membrane for activation via a series of phosphorylation events and dimerization with other RAF family members like B-Raf.^[1] Structurally, the 648-amino-acid protein (~73 kDa) comprises an N-terminal regulatory domain with Ras-binding and cysteine-rich regions, a central hinge, and a C-terminal kinase domain, allowing tight control through inhibitory intramolecular interactions that are relieved upon stimulation; recent cryo-EM studies as of 2025 have provided deeper insights into these dynamics.^[1]^[2] In physiological contexts, c-Raf integrates signals from receptor tyrosine kinases and G-protein-coupled receptors to phosphorylate and activate MEK1/2, which in turn stimulate ERK1/2 to influence gene expression and cytoskeletal dynamics, with knockout studies in mice revealing its essential role in embryonic development and vascular integrity, as embryos lacking c-Raf die around E10.5-E12.5 due to defective placental and hematopoietic functions.^[1] Beyond normal signaling, c-Raf is implicated in oncogenesis, where it is frequently overexpressed in various cancers including lung, liver, and prostate malignancies, facilitating tumor progression by amplifying RAS-driven signals even in the absence of direct RAF1 mutations, which are rare compared to those in B-RAF; emerging evidence also highlights RAF1 fusions and amplifications in some tumors.^[1]^[3]^[4] Its dysregulation also contributes to therapeutic resistance, such as paradoxical activation of the MAPK pathway in response to B-RAF inhibitors in wild-type cells, highlighting c-Raf's role in adaptive signaling networks.^[5]

History and Discovery

Initial Identification of Raf Kinases

The Raf kinase family was first identified through the discovery of the viral oncogene v-raf in 1983, transduced by the acutely transforming murine sarcoma retrovirus 3611-MSV. This retrovirus, isolated from a mouse tumor, efficiently transformed NIH 3T3 fibroblasts upon transfection with its proviral DNA, producing foci at a rate of approximately 4 per nanogram, and the recovered virus induced fibrosarcomas in inoculated mice. The v-raf oncogene was characterized as a novel sequence without close homology to previously known viral oncogenes, though its transforming potential suggested an initial association with tyrosine kinase activity, akin to other retroviral oncoproteins like v-src. This finding, reported by U.R. Rapp and colleagues, marked the initial recognition of the Raf family as key players in cellular transformation. The cellular homolog of v-raf, termed c-Raf (also known as c-Raf-1 or Raf-1), was subsequently identified in mammalian cells in the mid-1980s.^[6] In 1984, chromosomal mapping studies located the human c-raf locus on chromosome 3, confirming its distinction from other oncogene families and its conservation across species.^[7] The full coding sequence of human c-raf was cloned and reported in 1986, revealing a 648-amino-acid protein with conserved motifs indicative of a serine/threonine-specific protein kinase, thus establishing its biochemical classification within the kinase superfamily.^[8] This cellular counterpart demonstrated structural similarity to v-raf, particularly in its kinase domain, underscoring the retroviral oncogene's origin as a captured and altered version of a normal cellular gene involved in signal transduction.^[8] Initial functional studies of Raf kinases in the late 1980s began to elucidate their role in growth factor signaling pathways. Experiments demonstrated that c-Raf undergoes rapid phosphorylation in response to growth factors such as platelet-derived growth factor and epidermal growth factor, as well as upon expression of membrane-bound oncogenes like v-src, indicating activation within minutes of stimulation in transformed cells. Complementary work with temperature-sensitive mutants of avian retroviruses carrying related Raf-like oncogenes, such as v-mil in the MH2 virus, showed that shifting to permissive temperatures restored transforming activity and morphological changes in infected chicken cells, linking Raf family members to sustained proliferative signaling.^[9] These early investigations, building on the transforming properties observed with v-raf, positioned the Raf kinases as critical intermediaries in mitogenic signal relay from cell surface receptors to intracellular effectors.

Specific Characterization of c-Raf

The human c-Raf, also known as RAF1, was cloned as a cDNA from a fetal liver library, revealing an open reading frame encoding a 648-amino acid protein containing a serine/threonine kinase domain.^[8] The serine/threonine kinase activity of c-Raf was demonstrated in 1991 through in vitro phosphorylation assays, in which immunoprecipitated c-Raf from stimulated cells phosphorylated exogenous substrates including myelin basic protein, confirming its role as an active protein kinase. Early subcellular localization studies utilizing immunofluorescence microscopy in 1993 revealed that c-Raf is predominantly distributed in the cytoplasm under basal conditions but translocates to the plasma membrane upon stimulation with growth factors such as colony-stimulating factor 1, highlighting its dynamic localization in response to signaling cues. Mapping studies in the early 1990s, building on initial in situ hybridization data, confirmed the chromosomal assignment of the RAF1 gene to the 3p25 region in humans, positioning it within a locus implicated in certain cancers and providing a genetic framework for further functional analyses.^[10]

Structure

Domain Organization

c-Raf, also known as RAF1, is a 648-amino-acid serine/threonine kinase that consists of an N-terminal regulatory region spanning residues 1-257 and a C-terminal kinase domain encompassing residues 306-648.^[11] The N-terminal region maintains the protein in an autoinhibited state through intramolecular interactions with the kinase domain, while the C-terminal domain harbors the catalytic activity essential for signal transduction in the MAPK/ERK pathway.^[12] The regulatory domain includes several key components that mediate interactions with upstream regulators. The conserved region 1 (CR1), corresponding to residues 51-131, contains a zinc finger-like structure that facilitates binding to GTP-bound Ras, thereby recruiting c-Raf to the plasma membrane for activation.^[13] Adjacent to CR1 is the conserved region 2 (CR2), a serine-rich segment from residues 256-269, which serves as a binding site for 14-3-3 proteins upon phosphorylation at serine 259, stabilizing the inactive conformation.^[14] The kinase domain adopts a conserved bilobal architecture typical of eukaryotic protein kinases, with an N-lobe involved in ATP binding and a C-lobe responsible for substrate recognition. The ATP-binding site features a glycine-rich loop (G-loop) at residues 377-382, which positions the nucleotide for phosphoryl transfer.^[14] The activation loop, spanning residues 491-502, includes critical phosphorylation sites serine 497 and serine 499, which are targeted by protein kinase C and modulate catalytic competence upon modification.^[15] Connecting the regulatory and kinase domains is a flexible inter-domain linker region (residues 258-305), which plays a role in autoinhibition by allowing the N-terminal region to occlude the kinase active site and can influence dimerization interfaces.

Structural Dynamics and Recent Insights

In the autoinhibited monomer state of c-Raf, the N-lobe of the kinase domain engages with the regulatory domain, particularly through interactions involving the cysteine-rich domain (CRD), which nestles against the kinase domain and helps bury the activation segment in an autoinhibitory conformation.^[2] This configuration locks the C-helix in an outward, inactive position, as revealed by cryo-EM structures at 3.4 Å resolution.^[2] Earlier NMR studies from 2017 provided initial insights into the dynamic regulatory interactions contributing to this autoinhibition, while a 2022 crystal structure further corroborated the burial of the activation segment in related Raf family members.^[16] Dimerization-induced activation of c-Raf involves the formation of a side-to-side interface between kinase domains, which relieves autoinhibition by rearranging the C-helix into an active inward position and exposing the dimerization surface. This process is particularly asymmetric in c-Raf/B-Raf heterodimers, where one protomer adopts a more active conformation to drive the partner's activation, as detailed in 2022 cryo-EM studies of the monomer-to-dimer transition.^[17] The side-to-side dimer interface, often mediated by 14-3-3 binding to phosphorylated serine residues, promotes back-to-back alignment in the active state, enabling subsequent MEK phosphorylation. Recent cryo-EM structures from 2025 of the c-Raf/MEK1/14-3-3 ternary complex, resolved at 3.4 Å for the autoinhibited state, illustrate how 14-3-3 stabilizes the inactive state by binding the CR2 motif, specifically the phosphorylated Ser259 site, which sequesters the kinase domain and prevents dimerization.^[2] In this complex, the 14-3-3 dimer engages both phosphoserine segments (pSer259 and pSer621) on opposite sides, maintaining the CRD in a cradle-like position that blocks regulatory domain release.^[2] These structures highlight two open-monomer intermediates where pSer259 is released, facilitating dephosphorylation and progression toward activation.^[2] The Hsp90 chaperone complex, known as the RHC (Raf-Hsp90-Cdc37), plays a critical role in stabilizing the nascent kinase domain of c-Raf during folding, as shown in 2024 structural data.^[18] Cryo-EM analysis at 3.7 Å resolution reveals an asymmetric interaction where the unfolded N-lobe β5-strand of c-Raf threads through the Hsp90 luminal cavity, engaging via van der Waals contacts with Hsp90's src-loops and helical hairpins, while Cdc37 bridges the N- and C-lobes to the chaperone.^[18] This configuration ensures proper maturation of the kinase domain, with molecular simulations confirming strong electrostatic stabilization (e.g., -171.11 kcal/mol for the pS13-K405 interaction).^[18]

Evolutionary Relationships

Conservation Across Species

c-Raf, encoded by the RAF1 gene, displays high sequence conservation across vertebrate species, particularly in its kinase domain. The human Raf1 protein shares 98.9% amino acid sequence identity with its mouse ortholog, reflecting strong evolutionary preservation of core catalytic functions.^[19] This high similarity extends to the kinase domain, where identity exceeds 90% among vertebrates, enabling conserved roles in signal transduction. In contrast, the N-terminal regulatory domain shows lower conservation, approximately 70%, allowing for species-specific regulatory nuances while maintaining essential Ras-binding motifs.^[20] In invertebrates, c-Raf orthologs exhibit moderate sequence similarity, underscoring functional homology in Ras-MAPK signaling. The Drosophila melanogaster Raf homolog, known as Polehole (Raf or D-Raf), shares about 40% overall amino acid identity with human c-Raf, with higher conservation in the kinase domain.^[21] This ortholog is essential for torso receptor tyrosine kinase (RTK) signaling during embryonic patterning. Similarly, the Caenorhabditis elegans lin-45 gene encodes a Raf homolog required for vulval induction downstream of let-60 Ras, displaying significant sequence similarity in key domains despite overall lower identity compared to vertebrates.^[22] Functional conservation is evident from genetic studies across species. In mice, targeted disruption of the Raf1 gene results in embryonic lethality around mid-gestation, characterized by growth retardation and defects in placental and fetal liver development, as reported in late 1990s analyses.^[23] This phenotype mirrors the developmental defects observed in Drosophila upon Raf loss, including disruptions in eye development where the EGFR/Ras/Raf pathway specifies photoreceptor cell fates.^[24] Such parallels highlight the preserved necessity of c-Raf for RTK-mediated signaling in organogenesis. The evolutionary roots of c-Raf trace to the tyrosine kinase-like (TKL) family, which emerged in the last eukaryotic common ancestor approximately 1.5 billion years ago, with partial homologs appearing in early eukaryotes but no direct Raf kinases in yeast.^[25] This ancient origin supports the broad conservation of Raf-mediated pathways from unicellular organisms to complex metazoans.

Relations to Other Raf Family Members

The Raf family of serine/threonine kinases in humans consists of three isoforms: c-Raf (encoded by RAF1), B-Raf (encoded by BRAF), and A-Raf (encoded by ARAF). These genes are located on different chromosomes: RAF1 on 3p25.2, BRAF on 7q34, and ARAF on Xp11.2.^[26]^[27]^[28] Despite these distinct genomic positions, the isoforms share approximately 75% amino acid identity in their kinase domains, while exhibiting notable differences in their N-terminal regulatory regions that influence activation and specificity.^[6] In terms of intrinsic activity, c-Raf displays the lowest basal kinase activity among the isoforms and typically requires dimerization for full activation, whereas B-Raf possesses the highest basal activity and can function as a monomer under certain conditions. A-Raf exhibits the weakest overall activity toward MEK substrates and shows tissue-restricted expression, predominantly in urogenital tissues. In contrast, c-Raf maintains the broadest expression pattern across tissues, enabling its involvement in diverse cellular contexts.48650-7/fulltext)^[29]^[30]^[31]^[32] Functional redundancy exists among the isoforms, particularly through the formation of c-Raf/B-Raf heterodimers, which are prevalent in Ras-mediated MAPK signaling and enhance pathway activation. Knockout studies in mice reveal compensatory mechanisms; for instance, c-Raf can partially compensate for B-Raf loss in cardiac development, mitigating some hypertrophic responses despite B-Raf's dominant role in certain contexts.01054-4.pdf)^[33] The evolutionary divergence of the Raf family stems from gene duplication events associated with the two rounds of whole-genome duplication (2R hypothesis) early in vertebrate evolution, approximately 500 million years ago, leading to the three paralogs observed in mammals; c-Raf has retained the most ubiquitous expression profile among them.

Regulation of Activity

Activation Pathways

The activation of c-Raf, a serine/threonine kinase central to the MAPK/ERK pathway, is initiated primarily through Ras-dependent recruitment to the plasma membrane. GTP-bound Ras interacts with high affinity (approximately 10 nM) to the cysteine-rich domain (CR1) of c-Raf, specifically via the Ras-binding domain (RBD), which facilitates the translocation of cytosolic c-Raf to the membrane.^[34] This binding involves key residues R89 and Y91 within the CR1 region of c-Raf, enabling the disruption of autoinhibitory interactions that maintain c-Raf in an inactive state.^[34] Consequently, Ras recruits c-Raf to lipid rafts enriched in signaling molecules, positioning it for subsequent activating events.^[34] Upstream signals from receptor tyrosine kinases, such as EGFR, trigger the GDP-to-GTP exchange on Ras via guanine nucleotide exchange factors (GEFs), thereby activating the Ras-c-Raf interaction. This recruitment enables Src family kinases to phosphorylate c-Raf at tyrosine 341 (Y341) within its kinase domain, a critical step that enhances kinase activity and promotes downstream signaling.^[15] Src-mediated phosphorylation at Y341 occurs in a Ras-dependent manner, stabilizing an open conformation conducive to further activation.^[35] Scaffold proteins like kinase suppressor of Ras 1 and 2 (KSR1/2) further augment c-Raf activation by assembling a multiprotein complex at the plasma membrane, recruiting c-Raf alongside Ras, MEK, and other components to increase signaling efficiency. Discovered in mammalian systems in 1998, KSR1 acts as a docking platform that coordinates these interactions without intrinsic kinase activity, thereby amplifying the localized activation of c-Raf.^[36] This scaffold-mediated recruitment ensures spatial organization, preventing cross-talk and optimizing the phosphorylation cascade.^[37] Dimerization represents another key activation mechanism, where c-Raf forms homodimers or heterodimers with B-Raf through a conserved interface in their kinase domains. Studies using fluorescence resonance energy transfer (FRET) in the 2010s demonstrated that this dimerization, induced by Ras binding, enables allosteric activation of the receiver protomer independent of ATP binding, thereby boosting catalytic efficiency.^[38] The asymmetric nature of these dimers allows one subunit to allosterically relieve autoinhibition in the partner, a process essential for full kinase competence.^[38]

Inhibitory and Feedback Mechanisms

One key inhibitory mechanism of c-Raf involves the binding of 14-3-3 proteins, which is facilitated by phosphorylation at serine 259 (S259) in the conserved region 2 (CR2) and serine 621 (S621) in the conserved region 3 (CR3).^[39] This binding stabilizes the autoinhibited monomeric conformation of c-Raf, preventing premature activation and ensuring signaling fidelity by antagonizing recruitment to the plasma membrane in response to weak stimuli.^[39] Recent cryo-electron microscopy (cryo-EM) structures of the CRAF₂/14-3-3₂ complex at 3.4 Å resolution reveal that the dimeric 14-3-3 proteins bridge the CR2 and CR3 regions, enforcing an autoinhibitory state that is disrupted upon RAS-mediated membrane recruitment. A 2025 study further provides cryo-EM structures of CRAF/MEK1/14-3-3 complexes at resolutions up to 2.3 Å, elucidating autoinhibited and open-monomer states and additional regulatory features.^[2] Negative regulation of c-Raf also occurs through inhibitory phosphorylation at specific sites, including S259 and threonine 401 (T401). Phosphorylation of S259 by protein kinase A (PKA) in response to elevated cAMP levels directly suppresses c-Raf kinase activity, rendering it resistant to activation and correlating with deactivation of downstream ERK signaling.^[40] Similarly, phosphorylation at T401 inhibits c-Raf function by disrupting key protein interactions within the MAPK cascade.^[41] For activation to proceed, dephosphorylation of these sites, particularly S259, is essential and is mediated by protein phosphatase 2A (PP2A), which associates with c-Raf to promote membrane localization and relieve inhibition.^[42] Feedback inhibition further fine-tunes c-Raf activity through downstream ERK-mediated phosphorylation. Activated ERK phosphorylates c-Raf at T401 (and homologous sites such as S289, S296, and S301), which dampens pathway signaling by promoting dissociation from upstream activators like RAS.^[41] This negative feedback loop also targets the kinase suppressor of RAS (KSR) scaffold, where ERK phosphorylation at sites like T260, T274, S320, and S443 disrupts the KSR-c-Raf complex, attenuating signal transmission to MEK.^[43] Studies from the 2000s in cellular models, including fibroblasts, demonstrated this ERK-dependent phosphorylation as a rapid mechanism to limit sustained MAPK activation following growth factor stimulation.^[44] To prevent prolonged signaling, c-Raf undergoes proteasomal degradation via ubiquitination, particularly after extended activation periods. The E3 ubiquitin ligase CHIP targets misfolded or kinase-inactive forms of c-Raf for polyubiquitination, leading to their clearance by the 26S proteasome; this process is autophosphorylation-dependent at S621, as unphosphorylated c-Raf is rapidly degraded to maintain homeostasis.^[45] Proteasome inhibitors such as MG132 confirm this pathway by stabilizing c-Raf levels, highlighting its role in terminating signaling to avoid aberrant cellular responses.^[45]

Biological Functions

Role in MAPK/ERK Signaling

c-Raf, also known as Raf-1, serves as a key mitogen-activated protein kinase kinase kinase (MAP3K) in the canonical Ras-Raf-MEK-ERK signaling cascade, where it directly phosphorylates and activates MEK1/2 by targeting serine residues at positions 218 and 222 in their activation loops.^[46] This phosphorylation event, characterized by a Michaelis constant (Km) of approximately 0.8-1 μM for MEK as substrate, enables MEK1/2 to subsequently phosphorylate and activate ERK1/2 at threonine and tyrosine residues in their TEY motif.^[47] Activated ERK1/2 then translocates to the nucleus to phosphorylate transcription factors such as Elk-1, thereby regulating gene expression programs involved in cell proliferation and differentiation.^[48] In response to extracellular stimuli like growth factors including platelet-derived growth factor (PDGF) and epidermal growth factor (EGF), c-Raf integrates signals primarily through upstream activation by GTP-bound Ras at the plasma membrane, leading to rapid amplification of mitogenic responses.^[49] This activation typically manifests as transient pulses of ERK phosphorylation, peaking within 5-10 minutes post-stimulation before returning to baseline due to feedback mechanisms, ensuring precise temporal control of downstream effects.^[50] Among Raf isoforms, c-Raf predominantly transduces stress-related signals, such as those induced by tumor necrosis factor-α (TNF-α), whereas B-Raf is the primary mediator of growth factor-driven ERK activation; notably, c-Raf/B-Raf heterodimers enhance signaling efficiency by promoting allosteric activation and increased kinase output within the cascade.^[48] Systems-level modeling using flux control analysis has revealed that only about 10-20% activation of the total cellular c-Raf pool is sufficient to achieve maximal ERK signaling flux, underscoring the pathway's ultrasensitive response and the isoform's role as a tunable amplifier rather than a strict rate-limiter.^[51] This quantitative aspect highlights how phosphorylation events, such as those at c-Raf's serine 338 and tyrosine 341 residues, fine-tune its contribution to overall pathway dynamics.^[49]

Involvement in Other Cellular Processes

Beyond its canonical role in the MAPK/ERK pathway, c-Raf contributes to the regulation of apoptosis through post-translational modifications of pro-apoptotic proteins. Specifically, activation of c-Raf stimulates the phosphorylation of the BH3-only protein BAD at serine 112 (Ser112), which promotes its sequestration in the cytosol by 14-3-3 proteins, thereby preventing BAD from binding and inhibiting the anti-apoptotic protein Bcl-2 at the mitochondria.^[52] This mechanism enhances cell survival in a kinase-dependent manner via downstream effectors like RSK. Studies in cultured cerebellar granule neurons have demonstrated that growth factor-induced c-Raf activation leads to BAD phosphorylation at Ser112 and Ser136, cooperatively inactivating BAD and protecting neurons from apoptosis induced by trophic factor withdrawal.^[53] c-Raf also participates in cytoskeletal organization through direct protein-protein interactions independent of its kinase activity toward MEK. In particular, c-Raf binds to Rho-associated kinase α (Rok-α, also known as ROCK1), inhibiting its kinase activity and thereby modulating RhoA signaling to facilitate proper actin dynamics.^[54] This interaction is essential for the formation of actin stress fibers in fibroblasts, as evidenced by studies showing that c-Raf-deficient mouse embryonic fibroblasts exhibit hyperactivation of Rok-α, resulting in excessive cortical actin bundling and impaired stress fiber assembly; restoring c-Raf expression or inhibiting Rok-α reverses this defect and promotes stress fiber formation and cell spreading.^[54] These MEK-independent effects highlight c-Raf's scaffold function in maintaining cytoskeletal integrity during cell migration and adhesion. In the context of angiogenesis, c-Raf supports vascular development by influencing endothelial cell behavior, including the regulation of vascular endothelial growth factor (VEGF) expression through crosstalk with NF-κB signaling. In mouse models of growth plate maturation, conditional deletion of c-Raf in chondrocytes disrupts VEGF-A secretion, delaying endothelial invasion and vascularization, underscoring c-Raf's role in coordinating angiogenic cues.^[55] Although primarily studied in non-endothelial compartments, emerging evidence from endothelial cell lines indicates that c-Raf activation enhances NF-κB-mediated transcription of VEGF in response to inflammatory stimuli, fostering autocrine loops that promote endothelial proliferation and tube formation in vitro.^[56] c-Raf links to metabolic regulation in hepatic cells by integrating with insulin signaling pathways that control glycogen homeostasis. Through the Raf-1/MEK/ERK/p90RSK cascade, c-Raf indirectly modulates glycogen synthase activity by promoting the phosphorylation and inactivation of glycogen synthase kinase-3 (GSK-3), which otherwise inhibits glycogen synthase via phosphorylations at multiple sites.^[57] This effect is particularly relevant in liver hepatocytes, where stimuli like AICAR activate c-Raf to enhance GSK-3 inhibition, thereby increasing glycogen synthesis in coordination with insulin-induced Akt signaling, though the pathway's contribution is context-dependent and secondary to PI3K/Akt.^[57]

Disease Associations

Non-Cancerous Disorders

c-Raf, encoded by the RAF1 gene, has been implicated in several non-cancerous disorders through its dysregulation in the MAPK/ERK signaling pathway, particularly in genetic developmental conditions known as RASopathies and in inflammatory and neurological pathologies. Gain-of-function mutations in RAF1 lead to hyperactivation of downstream effectors, disrupting normal cellular processes during development and immune responses.^[58] In Noonan syndrome, a RASopathy characterized by facial dysmorphology, short stature, and congenital heart defects, rare germline RAF1 mutations cause gain-of-function effects that enhance ERK signaling, resulting in hypertrophic cardiomyopathy and other cardiac abnormalities. For instance, the S257L mutation in the CR2 domain of c-Raf impairs inhibitory phosphorylation at serine 259, promoting constitutive kinase activity and leading to severe cardiac defects in affected individuals. These mutations were first identified in 2007, and RAF1 variants account for approximately 3-17% of Noonan syndrome cases, with a notable ~5% prevalence in cohorts lacking PTPN11 mutations. Patients with RAF1-associated Noonan syndrome exhibit a higher incidence of hypertrophic cardiomyopathy (up to 95%) compared to other genetic subtypes.^[58]^[59]^[60] Similarly, activating variants in RAF1 contribute to cardio-facio-cutaneous (CFC) syndrome, another RASopathy involving ectodermal, cardiac, and craniofacial anomalies that impair postnatal development. The P261Q variant, located in the CR2 domain, exemplifies these changes by reducing autoinhibitory interactions and elevating MAPK pathway activity, which disrupts cellular proliferation and differentiation during embryogenesis. RAF1 mutations represent 10-15% of cases across RASopathies, including CFC, where they are less common than BRAF variants but still drive overlapping phenotypes like pulmonic stenosis and intellectual disability. These genetic alterations highlight c-Raf's conserved role in developmental signaling, as seen in evolutionary studies of MAPK conservation.^[61]^[60]^[62] Beyond genetic disorders, c-Raf participates in inflammatory responses, particularly in TLR4-mediated signaling that exacerbates sepsis. In mouse models of lipopolysaccharide (LPS)-induced sepsis, c-Raf activation downstream of TLR4 promotes phosphorylation of MEK and ERK, culminating in excessive cytokine release such as TNF-α and IL-6, which drives systemic inflammation and organ failure. Studies from the 2010s using Raf inhibitors like sorafenib demonstrated reduced cytokine production and improved survival in LPS-challenged mice, underscoring c-Raf's role in amplifying the innate immune response to bacterial endotoxins. This pathway's overactivation contributes to the cytokine storm observed in human sepsis, linking c-Raf to acute inflammatory disorders.^[63] Neurological associations involve c-Raf overactivation in Alzheimer's disease models, where amyloid-β (Aβ) peptides induce Ras activation, leading to c-Raf-mediated ERK signaling and subsequent tau hyperphosphorylation. In Aβ-exposed neuronal cultures and transgenic mouse models, this cascade activates GSK-3β, a key tau kinase, promoting neurofibrillary tangle formation and synaptic dysfunction. Inhibition of the Ras-Raf-ERK pathway reduces tau phosphorylation at disease-relevant sites like Ser396/404, suggesting c-Raf as a contributor to Aβ-driven neurodegeneration without directly causing oncogenesis.^[64]

Oncogenic Roles and Alterations

c-Raf, encoded by the RAF1 gene, contributes to oncogenesis primarily through hyperactivation rather than frequent direct mutations, often amplifying MAPK/ERK signaling in various cancers. Amplification and copy number gains of RAF1 occur in approximately 16% of cutaneous melanomas according to The Cancer Genome Atlas (TCGA) data, with higher rates up to 29% observed in some cohorts of metastatic samples, and these alterations are associated with worse progression-free survival. In lung cancers, RAF1 alterations including amplifications are less common, detected in about 2-3% of non-small cell lung carcinoma cases in pan-cancer analyses, yet overexpression of c-Raf correlates with disease progression across multiple tumor types. Such genomic gains lead to elevated c-Raf protein levels, enhancing tumor cell proliferation and survival independent of its kinase activity in certain contexts. Activating mutations in c-Raf are rare in human cancers, occurring in less than 1% of cases overall due to its intrinsically low basal kinase activity compared to B-Raf. In thyroid cancer, point mutations in the c-Raf kinase domain, such as those mimicking phosphorylation sites like S338, are infrequent, comprising around 2% of alterations in some subtypes, and are more prevalent in tumors with concurrent RAS mutations where they potentiate downstream signaling. These mutations typically enhance c-Raf's responsiveness to upstream RAS activation, promoting oncogenic transformation in RAS-mutant backgrounds rather than acting as primary drivers. c-Raf engages in significant crosstalk with other oncogenes, amplifying malignant phenotypes through integrated pathway activation. In NRAS-driven melanomas, c-Raf serves as the primary effector of mutant NRAS, enhancing PI3K/AKT signaling to support tumor growth and resistance to targeted therapies. Additionally, c-Raf compensates for BRAF inhibition by forming heterodimers with wild-type or mutant B-Raf, leading to paradoxical ERK activation that drives resistance in BRAF-mutant cancers. Recent studies highlight c-Raf's evolving role in KRAS-mutant pancreatic cancer, where it promotes tumor invasion through both ERK-dependent and independent mechanisms, such as kinase-independent scaffolding functions that sustain pro-survival signaling. A 2023 review emphasizes c-Raf's context-specific contributions in KRAS-driven malignancies, underscoring its potential as a therapeutic vulnerability in these aggressive tumors.

Therapeutic Targeting

Development of Inhibitors

The development of c-Raf inhibitors includes early multikinase agents like sorafenib, a type II ATP-competitive inhibitor approved by the FDA in 2005 for advanced renal cell carcinoma, which binds the kinase's conserved ATP-binding pocket and extends into an allosteric pocket to stabilize the inactive DFG-out conformation, with an IC50 of approximately 6 nM for c-Raf while also inhibiting B-Raf (IC50 ~22 nM) and other kinases such as VEGFR2, resulting in a pan-Raf profile with notable off-target effects that limit selectivity.^[65]^[66]^[67] Subsequent advancements in type II inhibitors include compounds that further stabilize the inactive DFG-out conformation of the kinase domain. PLX-4032 (vemurafenib), clinically approved for BRAF-mutant melanoma, represents this approach but paradoxically induces c-Raf activation in wild-type cells through enhanced Raf dimerization and transactivation of the MAPK pathway.^[68] To circumvent issues with orthosteric binding and paradoxical activation, researchers have explored allosteric modulators that target the Ras-binding site within the CR1 regulatory domain of c-Raf, disrupting upstream recruitment by active Ras-GTP. Preclinical compounds developed in the 2020s exemplify this strategy by binding to interfaces that prevent Ras-c-Raf interaction, thereby inhibiting activation without directly engaging the kinase domain.^[69]^[70] More recently, proteolysis-targeting chimeras (PROTACs) have emerged as a degradation-based modality for c-Raf, recruiting E3 ubiquitin ligases to induce ubiquitin-mediated proteasomal breakdown. For example, MS934, a VHL-recruiting MEK1/2 PROTAC, collaterally degrades CRAF in KRAS-mutant cells, offering a complementary mechanism to traditional inhibition by eliminating the protein entirely rather than merely blocking its activity.^[71]

Clinical Applications and Challenges

Sorafenib, a multikinase inhibitor targeting c-Raf among other kinases, received FDA approval in 2007 for the treatment of unresectable hepatocellular carcinoma (HCC), based on the SHARP trial demonstrating improved overall survival from 7.9 to 10.7 months compared to placebo.^[72] The objective response rate in this trial was approximately 2%, primarily attributed to Raf pathway inhibition, though the drug's broader effects on angiogenesis also contribute.^[72] Similarly, sorafenib was approved by the FDA in 2005 for advanced renal cell carcinoma (RCC), where it extended progression-free survival to 5.5 months versus 2.8 months with placebo in the TARGET trial, with c-Raf inhibition playing a key role in suppressing tumor proliferation.^[73] In BRAF-mutant melanoma, combination therapies incorporating c-Raf modulation have shown enhanced efficacy; for instance, the BRAF inhibitor encorafenib combined with the MEK inhibitor binimetinib improved median progression-free survival to 14.9 months in the phase III COLUMBUS trial, compared to 7.3 months with vemurafenib monotherapy, by mitigating paradoxical c-Raf activation.^[74] These 2018 results, with updates through the 2020s confirming durable benefits, highlight how dual inhibition addresses c-Raf-dependent resistance in BRAF V600-mutant settings.^[74] A major clinical challenge is resistance to Raf-targeted therapies, often arising from feedback reactivation of c-Raf dimers following B-Raf inhibition, a mechanism identified in the 2010s that sustains MAPK signaling in melanoma and other cancers. RAS mutations further predict poor response to c-Raf inhibitors by enhancing wild-type Raf dimerization and pathway reactivation, limiting efficacy in RAS-mutant tumors. Emerging strategies as of 2025 target 14-3-3 protein complexes that regulate c-Raf activation, with structural studies revealing potential disruption sites to overcome dimer-mediated resistance.^[2] Ongoing preclinical efforts include development of PET imaging probes for pan-Raf kinases to better select patients and monitor therapeutic engagement, as well as type I pan-RAF inhibitors like ELV-3111 that combine safely with MEK inhibitors for enhanced activity in NRAS and BRAF mutant cancers.^[75]^[76]

Protein Interactions

Core Binding Partners

c-Raf, also known as Raf-1, interacts directly with members of the Ras family of small GTPases, including H-Ras, K-Ras, and N-Ras, primarily through its Ras-binding domain (RBD) within the conserved region 1 (CR1). These GTP-bound Ras proteins bind to the RBD with high affinity, characterized by a dissociation constant (Kd) of approximately 20 nM for H-Ras, facilitating the recruitment and translocation of cytosolic c-Raf to the plasma membrane where activation occurs.^[77] This interaction is essential for c-Raf's membrane localization and subsequent signaling, and the Ras-c-Raf interface has been extensively studied in over 100 publications, highlighting key residues such as Ras Q61 and Y32 that contribute to specificity and binding stability.^[34] 14-3-3 proteins, particularly isoforms σ and ζ, bind to phosphorylated residues on c-Raf, including serine 259 (S259) and serine 621 (S621), thereby inhibiting its kinase activity by maintaining an autoinhibited conformation. This binding was first identified in the mid-1990s through yeast two-hybrid screens and co-immunoprecipitation assays, revealing that 14-3-3 association with the N-terminal regulatory domain of c-Raf prevents premature activation and promotes cytoplasmic retention.^[78] Pulldown experiments from that era confirmed the phosphorylation-dependent nature of these interactions, with S259 phosphorylation by kinases like AKT enhancing 14-3-3 binding to block Ras recruitment.^[39] As the primary substrate of c-Raf, MEK1 and MEK2 interact via a docking motif known as the D-domain on MEK, which engages the kinase domain of c-Raf to position it for efficient phosphorylation at activation sites S217 and S221. The Michaelis constant (Km) for this phosphorylation reaction is approximately 0.5-1 μM, reflecting moderate substrate affinity that supports rapid signal propagation in the MAPK pathway.^[47] Structural studies have delineated the D-domain as a basic stretch of residues on MEK that binds an acidic patch on c-Raf, ensuring specificity in the kinase-substrate complex.^[79] c-Raf stability is maintained through interaction with the chaperone Hsp90, mediated by the co-chaperone Cdc37, which binds the kinase domain of immature c-Raf to prevent degradation and facilitate maturation. Co-immunoprecipitation studies have demonstrated that disruption of the Hsp90-Cdc37-c-Raf complex leads to ubiquitination and proteasomal degradation of c-Raf, underscoring Hsp90's role in stabilizing the protein under physiological conditions.^[80] This binary interaction, often observed in early biosynthetic stages, ensures proper folding without directly impacting catalytic activity once c-Raf is fully assembled.

Regulatory Complexes

c-Raf, also known as RAF1, is regulated through dynamic protein complexes that control its activation, localization, and signaling output in the MAPK/ERK pathway. These complexes primarily involve upstream activators like RAS, scaffolding proteins such as KSR, regulatory adapters like 14-3-3, and inhibitory factors including RKIP, which collectively modulate c-Raf's autoinhibited state, membrane recruitment, and dimerization. Structural studies have revealed that c-Raf's N-terminal regulatory region, comprising the RAS-binding domain (RBD) and cysteine-rich domain (CRD), interacts with these partners to relieve intramolecular inhibition and facilitate kinase domain activation.^[81]^[2] A central regulatory complex forms upon RAS-GTP binding to c-Raf's RBD, which recruits c-Raf to the plasma membrane and disrupts autoinhibitory interactions between the N-terminal region and the kinase domain. This RAS-c-Raf engagement is stabilized by the CRD's membrane interactions and is essential for subsequent dimerization with other RAF isoforms or KSR. Cryo-EM structures show that in the autoinhibited state, RAS binding initiates a conformational shift, exposing sites for phosphorylation and enabling c-Raf's transition to an open monomer ready for activation. Additionally, the scaffold protein KSR1 assembles a multiprotein complex including c-Raf, MEK, and ERK, promoting efficient signal transduction; KSR1's pseudokinase domain heterodimerizes with c-Raf in a side-to-side manner, allosterically positioning c-Raf's catalytic helix αC for MEK phosphorylation.^[81]^[2]^[11] The 14-3-3 proteins form a critical regulatory complex with c-Raf by binding phosphorylated serine residues (pSer259 in the N-region and pSer621 in the kinase domain), stabilizing the autoinhibited monomer and preventing premature dimerization. Upon signaling, dephosphorylation of pSer259 by the SHOC2-MRAS-PP1C phosphatase complex releases this inhibition, allowing 14-3-3 to reorient and bridge two c-Raf protomers via their pSer621 sites, thereby promoting active back-to-back dimers. This 14-3-3-mediated dimerization is further supported by N-terminal phosphorylation (e.g., at Ser338 and Tyr341 by PAK or Src kinases), which enhances complex stability and c-Raf activity. In parallel, the chaperone complex HSP90-CDC37 binds c-Raf to maintain its folding and stability, while associated PP5 dephosphorylates regulatory sites post-activation to facilitate signal termination.^[2]^[81]^[11] Inhibitory regulatory complexes also play key roles; for instance, Raf Kinase Inhibitory Protein (RKIP) binds the N-terminal region of c-Raf (residues ~Tyr340-Lys615), forming a stable complex via hydrogen bonds and hydrophobic interactions at hotspots like Tyr340, Arg398, and RKIP's Lys80 and Trp84. This binding prevents c-Raf phosphorylation at activating sites (Ser338, Tyr340/341) and disrupts c-Raf-MEK association, thereby suppressing MAPK signaling. Molecular dynamics simulations indicate a binding free energy of approximately -174 kJ/mol for the RKIP-c-Raf complex, underscoring its potency. Scaffolds like CNK1 can either enhance or inhibit c-Raf activation depending on context, often by modulating Src-mediated phosphorylation within these assemblies. Overall, these complexes ensure precise spatiotemporal control of c-Raf, integrating positive and negative inputs to fine-tune cellular responses.^[82]^[11]^[83]

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