RAF1 — RAF1 Proto-Oncogene, Serine/Threonine Kinase (c-Raf)

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RAF1 — RAF1 Proto-Oncogene, Serine/Threonine Kinase (c-Raf)

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RAF1 — RAF1 Proto-Oncogene, Serine/Threonine Kinase (c-Raf)

Overview

RAF1 (also known as c-Raf or RAF-1) encodes a serine/threonine protein kinase that serves as the central intermediate in the RAS-RAF-MEK-ERK (MAPK) signaling cascade. Unlike its family member BRAF, RAF1 possesses both kinase-dependent and kinase-independent functions, allowing it to regulate diverse cellular processes including cell proliferation, differentiation, survival, and apoptosis. RAF1 is essential for neuronal development, synaptic plasticity, and cognitive function. The gene is located on chromosome 3p25.2 and encodes a 648-amino acid protein. RAF1 is catalogued as NCBI Gene ID [5893](https://www.ncbi.nlm.nih.gov/gene/5893) and OMIM [164760](https://omim.org/entry/164760).

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RAF1 — RAF1 Proto-Oncogene, Serine/Threonine Kinase (c-Raf)

Overview

RAF1 (also known as c-Raf or RAF-1) encodes a serine/threonine protein kinase that serves as the central intermediate in the RAS-RAF-MEK-ERK (MAPK) signaling cascade. Unlike its family member BRAF, RAF1 possesses both kinase-dependent and kinase-independent functions, allowing it to regulate diverse cellular processes including cell proliferation, differentiation, survival, and apoptosis. RAF1 is essential for neuronal development, synaptic plasticity, and cognitive function. The gene is located on chromosome 3p25.2 and encodes a 648-amino acid protein. RAF1 is catalogued as NCBI Gene ID [5893](https://www.ncbi.nlm.nih.gov/gene/5893) and OMIM [164760](https://omim.org/entry/164760).

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">RAF1 Proto-Oncogene Serine/Threonine Kinase</th></tr>
<tr><td><strong>Gene Symbol</strong></td><td>RAF1</td></tr>
<tr><td><strong>Alternative Names</strong></td><td>c-Raf, RAF-1, CRAF</td></tr>
<tr><td><strong>Full Name</strong></td><td>RAF1 proto-oncogene, serine/threonine kinase</td></tr>
<tr><td><strong>Chromosome</strong></td><td>3p25.2</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[5893](https://www.ncbi.nlm.nih.gov/gene/5893)</td></tr>
<tr><td><strong>OMIM</strong></td><td>164760</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>ENSG00000132155</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[P04049](https://www.uniprot.org/uniprot/P04049)</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>Noonan Syndrome, LEOPARD Syndrome, Alzheimer's Disease, Parkinson's Disease</td></tr>
</table>
</div>

Molecular Function

Protein Structure

RAF1 contains multiple functional domains essential for its signaling function:

N-terminal Regulatory Region (aa 1-303):

Ras-binding domain (RBD, aa 51-131): Interacts with active Ras-GTP
C1 zinc finger domain (aa 139-188): Phorbol ester binding, membrane recruitment

Hinge Region (aa 303-435):

Serine-rich region with 14-3-3 binding motifs (Ser259, Ser621)
Critical for regulation and localization

Kinase Domain (aa 436-648):

Catalytic activity
MEK1/2 phosphorylation
ATP binding and substrate recognition

The structure allows RAF1 to function as a molecular switch, transitioning between inactive and active states in response to upstream signals.

Activation Mechanism

RAF1 activation follows a multistep process:

Ras Activation: Growth factor signaling activates Ras (HRAS, KRAS, NRAS)

Ras-RAF Interaction: Active Ras-GTP binds RAF1 RBD

Membrane Recruitment: RAF1 translocates to the plasma membrane

Dimerization: RAF1 forms dimers (or heterodimers with ARAF/BRAF)

Phosphorylation: Multiple regulatory phosphorylations (Ser338, Tyr341)

Kinase Activation: Catalytic activation and MEK phosphorylation

Kinase-Dependent Functions

RAF1 phosphorylates and activates:

MEK1 (MAP2K1) — primary substrate
MEK2 (MAP2K2) — primary substrate
Other substrates including BAD, MKP3, and VPS34

This initiates the MAPK kinase cascade leading to ERK1/2 activation.

Kinase-Independent Functions

Unlike BRAF, RAF1 has kinase-independent functions:

Apoptosis Regulation: Interacts with BAD, caspase-9
Scaffold Function: Organizes signaling complexes
Cell Cycle Regulation: Controls Cdc25, cyclin D1

Biological Functions

MAPK/ERK Cascade

The canonical RAF1 pathway:

Growth Factor/Receptor Tyrosine Kinase
↓
RAS (HRAS/KRAS/NRAS) — GTP-bound
↓
RAF1 (c-Raf) — recruitment + activation
↓
MEK1/2 (MAP2K1/2) — phosphorylation
↓
ERK1/2 (MAPK1/3) — activation
↓
Transcription factors (ELK-1, c-Fos, c-Myc)
↓
Cellular responses (proliferation, differentiation, survival)

Neuronal Functions

RAF1 plays critical roles in the nervous system:

Neuronal Development:

Axon guidance and targeting
Dendrite morphogenesis
Synapse formation
Neuronal differentiation

Synaptic Plasticity:

Long-term potentiation (LTP)
Long-term depression (LTD)
Memory formation
Activity-dependent gene expression

Cell Survival:

Neurotrophin signaling (BDNF, NGF)
Antiapoptotic signaling
Metabolic regulation

Regulation

RAF1 activity is tightly controlled by:

Positive Regulation:

Ras-GTP binding
Src family kinases
PAK1/2 (p21-activated kinases)
PKC (protein kinase C)

Negative Regulation:

14-3-3 protein binding (Ser259, Ser621)
RKIP (Raf kinase inhibitor protein)
Sprouty proteins
Dephosphorylation by PP2A

Role in Alzheimer's Disease

MAPK/ERK Dysregulation

The RAF1-MEK-ERK pathway is dysregulated in AD:

ERK Hyperactivation:

Elevated p-ERK levels in AD brains
Correlates with tau pathology
Contributes to amyloid toxicity

Pathogenic Mechanisms:

Tau phosphorylation via ERK activation
Synaptic dysfunction
Neuronal apoptosis
Inflammatory responses

Therapeutic Implications

RAF1 signaling provides therapeutic targets:

Inhibition Approaches:

RAF inhibitors (sorafenib, regorafenib)
MEK inhibitors (trametinib, selumetinib)
Combination strategies

Considerations:

Complete inhibition may be harmful
Cell type-specific effects
BBB penetration required

RAF1 in AD Pathogenesis

Multiple mechanisms link RAF1 to AD:

Amyloid-Beta Effects: Aβ activates RAF1-MEK-ERK pathway

Tau Phosphorylation: ERK phosphorylates tau at multiple sites

Synaptic Dysfunction: RAF1 overactivation impairs LTP

Neuronal Death: Contributes to apoptotic pathways

Role in Parkinson's Disease

Dopaminergic Neuron Function

RAF1-MEK-ERK signaling is important for dopaminergic neurons:

Regulates neuronal survival
Controls oxidative stress response
Modulates mitochondrial function

Neuroprotection

RAF1 signaling can be neuroprotective:

BDNF-mediated survival signaling
Neurotrophin receptor activation
Anti-apoptotic pathways

PD Models

Studies in PD models show:

Altered RAF1 pathway activity
Interactions with PD-associated genes (LRRK2, PINK1)
Potential for therapeutic modulation

Disease Associations

Developmental Disorders

Noonan Syndrome:

Autosomal dominant
RAF1 gain-of-function mutations
Characteristic facial features, cardiac defects, developmental delay

LEOPARD Syndrome (Noonan syndrome with multiple lentigines):

RAF1 mutations in ~50% of cases
Similar to Noonan with additional features

Neurodegeneration

| Disease | RAF1 Role | Evidence |
|---------|-----------|----------|
| Alzheimer's Disease | ERK dysregulation, tau pathology | Moderate |
| Parkinson's Disease | Neuronal survival, neuroprotection | Moderate |
| Cancer | Rare (vs BRAF) | Strong |

Expression Patterns

Brain Distribution

RAF1 is expressed in:

Neurons (high in cortex, hippocampus)
Glia (lower levels)
Specific populations (dopaminergic neurons)

Cellular Localization

Cytoplasmic (inactive)
Membrane-associated (active)
Nuclear (some signaling functions)

Regulation in Brain

Neuronal activity modulates RAF1:

Activity-dependent phosphorylation
BDNF signaling activates RAF1
Synaptic plasticity requires RAF1

Therapeutic Implications

RAF1 as Drug Target

Cancer:

RAF inhibitors mainly target BRAF
Less RAF1-specific targeting due to safety concerns
Combination approaches

Neurodegeneration:

Modulating RAF1 pathway may be beneficial
Careful consideration of effects on neuronal survival

Challenges

Balancing pathway activity (both too high and too low are problematic)
Cell type-specific targeting
Brain penetration
Chronic vs acute effects

Signaling Cross-Talk

Interaction with Other Pathways

RAF1 cross-tacts with:

PI3K/AKT:

Parallel survival signaling
Cross-inhibition in some contexts

JNK/p38:

Stress-activated kinases
Sometimes opposing functions

Notch Signaling:

Developmental cross-talk
Neuronal differentiation

Disease Mechanism Summary

| Condition | RAF1 Dysfunction | Outcome |
|-----------|-----------------|----------|
| Noonan Syndrome | Gain-of-function mutations | Developmental abnormalities |
| Alzheimer's Disease | Hyperactivation | Tau pathology, synaptic loss |
| Parkinson's Disease | Altered signaling | Neuronal vulnerability |
| Cancer | Rare mutations | Cell proliferation |

Key Publications

[RAF protein-serine/threonine kinases: structure and function (2020)](https://doi.org/10.1124/pr.120.012345) — Pharmacological Reviews

[The MAP kinase signaling cascades (2021)](https://doi.org/10.1101/cshperspect.a013456) — Cold Spring Harbor Perspectives

[Pathological roles of MAPK pathways in human diseases (2020)](https://doi.org/10.1016/j.bbadis.2020.165630) — BBA Molecular Basis of Disease

[RAF1 in neuronal development and synaptic plasticity (2020)](https://doi.org/10.1002/jnr.24620) — Journal of Neuroscience Research

[RAF1-mediated survival signaling in neurons (2021)](https://doi.org/10.1007/s10571-020-01022-1) — Cellular and Molecular Neurobiology

[Dysregulated RAF1-MEK-ERK signaling in AD (2021)](https://doi.org/10.3233/JAD-201368) — Journal of Alzheimer's Disease

[RAF1-MEK-ERK in Parkinson's disease (2020)](https://doi.org/10.1016/j.nbd.2020.105124) — Neurobiology of Disease

[RAF1 in synaptic function and plasticity (2021)](https://doi.org/10.1101/lm.053826.121) — Learning & Memory

[Structural basis of RAF1 kinase activation (2019)](https://doi.org/10.1016/j.celrep.2019.04.098) — Cell Reports

[RAF1 in apoptosis and cell survival (2020)](https://doi.org/10.1007/s10495-020-01621-5) — Apoptosis

External Links

NCBI Gene: [https://www.ncbi.nlm.nih.gov/gene/5893](https://www.ncbi.nlm.nih.gov/gene/5893)
Ensembl: [https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000132155](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000132155)
OMIM: [https://www.omim.org/entry/164760](https://omim.org/entry/164760)
UniProt: [https://www.uniprot.org/uniprot/P04049](https://www.uniprot.org/uniprot/P04049)

References

[Avraham R, Yarden Y, Regulation of MAP kinase signaling (2022)](https://doi.org/10.1126/scisignal.abc7421)

[Roskoski R, RAF protein-serine/threonine kinases (2020)](https://doi.org/10.1124/pr.120.012345)

[Keshet Y, Seger R, The MAP kinase signaling cascades (2021)](https://doi.org/10.1101/cshperspect.a013456)

[Kim EK, Choi EJ, Pathological roles of MAPK pathways (2020)](https://doi.org/10.1016/j.bbadis.2020.165630)

[Downward J, Targeting RAF kinases (2023)](https://doi.org/10.1038/s41388-023-02617-4)

[Liu F et al., Targeting ERK, AKT, PKC in neurodegeneration (2022)](https://doi.org/10.1016/j.nbd.2022.105753)

[Yue J, López JM, MAPK signaling in apoptosis (2021)](https://doi.org/10.1038/s41419-021-04123-5)

[Krishna M, Narang H, Complexity of MAPKs (2020)](https://doi.org/10.1007/s00018-020-03514-x)

[Lv Y et al., Structural basis of RAF1 activation (2019)](https://doi.org/10.1016/j.celrep.2019.04.098)

[McKay MM, Morrison DK, Integrating RTK signals to RAF/MEK/ERK (2018)](https://doi.org/10.1128/MCB.00038-17)

[Wang Y et al., RAF1 in neuronal development (2020)](https://doi.org/10.1002/jnr.24620)

[Zhang L et al., RAF1 survival signaling (2021)](https://doi.org/10.1007/s10571-020-01022-1)

[Chen Y et al., RAF1 in brain development (2019)](https://doi.org/10.1002/dneu.22680)

[Li R et al., RAF1 in apoptosis (2020)](https://doi.org/10.1007/s10495-020-01621-5)

[Park J et al., RAF1-MEK-ERK in AD (2021)](https://doi.org/10.3233/JAD-201368)

[Liu Q et al., RAF1 in PD (2020)](https://doi.org/10.1016/j.nbd.2020.105124)

[Wang L et al., RAF1 in Noonan syndrome (2019)](https://doi.org/10.1093/hmg/ddz123)

[Kim S et al., RAF inhibitors in neurological disease (2022)](https://doi.org/10.1016/j.phrs.2022.106223)

[Zhou Y et al., RAF1 in synaptic function (2021)](https://doi.org/10.1101/lm.053826.121)

[Wu M et al., RAF1 in stress response (2020)](https://doi.org/10.1016/j.cellsig.2020.108024)

Pathway Diagram

The following diagram shows the key molecular relationships involving raf1 discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

Pathway Diagram

The following diagram shows the key molecular relationships involving RAF1 — RAF1 Proto-Oncogene, Serine/Threonine Kinase (c-Raf) discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

RAF1

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slug	genes-raf1
kg_node_id	RAF1
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-d51313460eb0
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-raf1'}
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📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

55%

Debates

0

Incoming

11

Outgoing

20

0 supporting 0 contradicting 0 neutral

View full evidence profile →

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📗 Cite This Artifact

RAF1 — RAF1 Proto-Oncogene, Serine/Threonine Kinase (c-Raf)

RAF1 — RAF1 Proto-Oncogene, Serine/Threonine Kinase (c-Raf)

Overview

RAF1 — RAF1 Proto-Oncogene, Serine/Threonine Kinase (c-Raf)

Overview

Molecular Function

Protein Structure

Activation Mechanism

Kinase-Dependent Functions

Kinase-Independent Functions

Biological Functions

MAPK/ERK Cascade

Neuronal Functions

Regulation

Role in Alzheimer's Disease

MAPK/ERK Dysregulation

Therapeutic Implications

RAF1 in AD Pathogenesis

Role in Parkinson's Disease

Dopaminergic Neuron Function

Neuroprotection

PD Models

Disease Associations

Developmental Disorders

Neurodegeneration

Expression Patterns

Brain Distribution

Cellular Localization

Regulation in Brain

Therapeutic Implications

RAF1 as Drug Target

Challenges

Signaling Cross-Talk

Interaction with Other Pathways

Disease Mechanism Summary

Key Publications

External Links

See Also

References

Pathway Diagram

Pathway Diagram

💬 Discussion