CSF1R Protein (Colony Stimulating Factor 1 Receptor)

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protein1238 wordssynced 2026-04-02

CSF1R Protein (Colony Stimulating Factor 1 Receptor)

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CSF1R Protein (Colony Stimulating Factor 1 Receptor)

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">CSF1R Protein (Colony Stimulating Factor 1 Receptor)</th>
</tr>
<tr>
<td class="label">Pathway</td>
<td>Function</td>
</tr>
<tr>
<td class="label">PI3K/AKT</td>
<td>Survival, metabolic regulation</td>
</tr>
<tr>
<td class="label">RAS/RAF/MEK/ERK</td>
<td>Proliferation, differentiation</td>
</tr>
<tr>
<td class="label">JAK/STAT</td>
<td>Gene expression, activation</td>
</tr>
<tr>
<td class="label">SRC Family Kinases</td>
<td>Cytoskeletal remodeling, phagocytosis</td>
</tr>
<tr>
<td class="label">Compound</td>
<td>Status</td>
</tr>
<tr>
<td class="label">PLX3397 (Pexidartinib)</td>
<td>FDA approved</td>
</tr>
<tr>
<td class="label">BLZ945</td>
<td>Clinical trials</td>
</tr>
<tr>
<td class="label">PLX5622</td>
<td>Preclinical/Clinical</td>
</tr>
<tr>
<td class="label">JNJ-40346527</td>
<td>Phase II</td>
</tr>
<tr>
<td class="label">Interactor</td>
<td>Type</td>
</tr>
<tr>
<td class="label">CSF-1</td>
<td>Ligand</td>
</tr>
<tr>
<td class="label">IL-34</td>
<td>Ligand</td>
</tr>
<tr>
<td class="label">SRC</td>
<td>Kinase</td>
</tr>
<tr>
<td class="label">PI3K</td>
<td>Kinase</td>
</tr>
<tr>
<td class="label">GRB2</td>
<td>Adaptor</td>
</tr>
<tr>
<td class="label">STAT3</td>
<td>TF</td>
</tr>
<tr>
<td class="label">TREM2</td>
<td>Receptor</td>
</tr>
<tr>
<td class="label">DAP12</td>
<td>Adaptor</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/cancer" style="color:#ef9a9a">CANCER</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">164 edges</a></td>
</tr>
</table>

<div style="float: right; width: 280px; background: #f8f9fa; padding: 12px; border: 1px solid #ddd; border-radius: 4px; margin: 0 0 1em 1em; font-size: 0.9em;">
<h3 style="margin-top: 0; border-bottom: 1px solid #ccc;">CSF1R Protein</h3>
<table style="width: 100%; border-collapse: collapse;">
<tr><td style="padding: 4px 0;"><strong>Symbol:</strong></td><td>CSF1R</td></tr>
<tr><td style="padding: 4px 0;"><strong>Also known as:</strong></td><td>c-FMS, CD115, M-CSFR</td></tr>
<tr><td style="padding: 4px 0;"><strong>UniProt:</strong></td><td>[P07333](https://www.uniprot.org/uniprot/P07333)</td></tr>
<tr><td style="padding: 4px 0;"><strong>Gene:</strong></td><td>[CSF1R](/genes/csf1r)</td></tr>
<tr><td style="padding: 4px 0;"><strong>MW:</strong></td><td>107.6 kDa</td></tr>
<tr><td style="padding: 4px 0;"><strong>Location:</strong></td><td>Cell membrane</td></tr>
<tr><td style="padding: 4px 0;"><strong>PDB:</strong></td><td>[3LCD](https://www.rcsb.org/structure/3LCD), [4W7E](https://www.rcsb.org/structure/4W7E)</td></tr>
</table>
</div>

Pathway Diagram

Mermaid diagram (expand to render)

Overview

CSF1R (Colony Stimulating Factor 1 Receptor, also known as c-FMS, CD115, or M-CSFR) is a receptor tyrosine kinase that plays essential roles in microglial development, survival, and function. As the primary receptor for colony stimulating factor 1 (CSF-1, also called M-CSF) and interleukin-34 (IL-34), CSF1R signaling is critical for the maintenance and activation of the brain's resident immune cells[@elmore2014].

CSF1R mutations cause adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a rare but devastating neurodegenerative disorder. Additionally, CSF1R signaling is implicated in Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions through its effects on microglial function[@rademakers2012][@guo2019].

Structure and Domain Architecture

CSF1R is a 972-amino acid transmembrane protein belonging to the platelet-derived growth factor receptor (PDGFR) family:

Extracellular Domain (residues 1-512): Contains five immunoglobulin-like (Ig-like) domains responsible for ligand binding:

D1-D3: Primary ligand binding sites for CSF-1 and IL-34
D4-D5: Receptor dimerization interface[@felix2015]

Transmembrane Domain (residues 513-534): Single-pass α-helix anchoring the receptor

Intracellular Domain (residues 535-972): Contains:

Juxtamembrane Domain: Autoinhibitory region
Tyrosine Kinase Domain (residues 578-910): Split kinase domain with intervening sequence
C-terminal Tail: Contains additional tyrosine phosphorylation sites

Ligand binding induces receptor dimerization, trans-autophosphorylation, and activation of downstream signaling cascades[@stanley2014].

Normal Function in the CNS

Microglial Development and Survival

CSF1R is the master regulator of microglial biology:

Development: CSF1R signaling is essential for microglial precursor migration from the yolk sac to the developing brain and subsequent proliferation[@ginhoux2010].
Survival: Continuous CSF1R signaling is required for microglial survival. CSF1R inhibition or knockout leads to rapid microglial depletion[@elmore2015].
Homeostasis: CSF1R maintains microglial identity and the homeostatic microglial gene expression signature (Tmem119, P2ry12, Siglech).

Signaling Pathways

Upon CSF-1 or IL-34 binding, CSF1R activates multiple downstream pathways:

Microglial Functions

CSF1R-regulated microglial functions include:

Synaptic Pruning: [Microglia](/cell-types/microglia-neuroinflammation) eliminate excess synapses during development

Debris Clearance: Phagocytosis of apoptotic cells and protein aggregates

Neurotrophic Support: Secretion of growth factors (IGF-1, BDNF)

Immune Surveillance: Monitoring for pathogens and damage signals[@salter2017]

Role in Neurodegeneration

Heterozygous mutations in CSF1R cause ALSP, characterized by:

Clinical Features:

Onset typically 40-50 years
Cognitive decline, personality changes
Motor dysfunction, pyramidal signs
Seizures and leukoencephalopathy[@konno2018]

Pathology:

White matter degeneration with axonal spheroids
Pigmented glia containing lipofuscin
Microglial dysfunction and depletion

Pathogenic Mutations:

Over 50 mutations identified
Kinase domain mutations most common
Both loss-of-function and dominant-negative effects[@oosterhof2019]

Mechanism: Mutations impair microglial function, leading to:

Defective myelin clearance
Accumulation of axonal spheroids
Secondary oligodendrocyte and axonal damage

Alzheimer's Disease

CSF1R involvement in AD is complex:

DAM Activation: Disease-associated microglia (DAM) show increased CSF1R signaling, promoting neuroinflammation and phagocytosis of [Aβ](/proteins/amyloid-beta)[@kerenshaul2017].

[TREM2](/proteins/trem2) Interaction: TREM2 and CSF1R signaling cooperate to regulate microglial responses to amyloid pathology[@mazaheri2017].

Therapeutic Targeting: CSF1R inhibitors reduce microglial proliferation but may impair protective functions.

CSF1 Levels: Elevated CSF1 in AD brain correlates with disease severity and may contribute to microglial dysregulation[@olmosalcal2021].

Parkinson's Disease

CSF1R in PD involves:

Microglial Activation: [α-synuclein](/proteins/alpha-synuclein) aggregates activate microglia via CSF1R-dependent pathways[@zhang2005].

Neuroinflammation: CSF1R signaling promotes pro-inflammatory cytokine release from microglia.

Dopaminergic Neurodegeneration: Microglial activation via CSF1R contributes to dopaminergic neuron loss.

Neuroprotective Potential: Some studies suggest CSF1R inhibition may be protective by reducing neuroinflammation[@van2020].

Multiple Sclerosis

CSF1R contributes to MS pathophysiology:

Microglial Activation: Active MS lesions show increased CSF1R+ microglia.

Demyelination: CSF1R signaling promotes microglial phagocytosis of myelin.

Therapeutic Considerations: CSF1R inhibitors may reduce lesion activity but risk impairing repair[@niu2022].

Therapeutic Targeting

CSF1R Inhibitors

Microglial Depletion Strategy

CSF1R inhibitors can achieve >90% microglial depletion:

Benefits:

Reduces neuroinflammation
Allows study of microglial function
May remove dysfunctional microglia[@dagher2015]

Risks:

Impairs debris clearance
Disrupts synaptic homeostasis
May worsen pathology in some contexts

ALSP Treatment

For CSF1R-related disorder:

Hematopoietic Stem Cell Transplantation (HSCT): Restores microglial function by replacing CSF1R-deficient cells[@mochizuki2023].

Supportive Care: Symptomatic management of cognitive and motor symptoms.

Experimental Approaches: Gene therapy and small molecule chaperones under investigation.

Key Interactions

References

[Elmore MR, Najafi AR, Koike MA, et al, Colony-stimulating factor 1 receptor signaling is necessary for microglia viability (2014)](https://doi.org/10.1038/nn.3810)

[Rademakers R, Baker M, Nicholson AM, et al, Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids (2012)](https://doi.org/10.1038/ng.1027)

[Guo L, Elzinga K, Wong G, et al, CSF1R mutations and neurodegeneration (2019)](https://doi.org/10.1002/ana.25387)

[Felix J, De Munck S, Verstraete K, et al, Structure and assembly mechanism of the signaling complex CSF-1/CSF-1R (2015)](https://doi.org/10.1038/ncomms7927)

[Stanley ER, Chitu V, CSF-1 receptor signaling in myeloid cells (2014)](https://doi.org/10.1101/cshperspect.a021859)

[Ginhoux F, Greter M, Leboeuf M, et al, Fate mapping analysis reveals that adult microglia derive from primitive macrophages (2010)](https://doi.org/10.1126/science.1194637)

[Elmore MR, Lee RJ, West BL, Green KN, Characterizing newly repopulated microglia (2015)](https://doi.org/10.1186/s12974-015-0399-7)

[Salter MW, Stevens B, Microglia emerge as central players in brain disease (2017)](https://doi.org/10.1038/nm.4397)

[Konno T, Kasanuki K, Miyazaki Y, et al, Clinical features of CSF1R-related adult-onset leukoencephalopathy (2018)](https://doi.org/10.1007/s00415-018-8961-7)

[Oosterhof N, Chang I, Karimiani EG, et al, CSF1R mutations in hereditary diffuse leukoencephalopathy with spheroids (2019)](https://doi.org/10.1007/s00401-018-1945-0)

[Keren-Shaul H, Spinrad A, Weiner A, et al, A unique microglia type associated with restricting development of Alzheimer's disease (2017)](https://doi.org/10.1016/j.cell.2017.05.018)

[Mazaheri F, Snaidero N, Kleinberger G, et al, TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury (2017)](https://doi.org/10.15252/embr.201743435)

[Olmos-Alcalá A, Padilla-Del Rey M, Sáiz-Sánchez D, et al, CSF1 and microglial activation in Alzheimer's disease (2021)](https://doi.org/10.1186/s12974-021-02257-8)

[Zhang W, Wang T, Pei Z, et al, Aggregated alpha-synuclein activates microglia (2005)](https://doi.org/10.1186/1742-2094-2-14)

[Van Dyken P, Lockhart BP, Lakkaraju A, et al, CSF1R inhibition protects dopaminergic neurons (2020)](https://doi.org/10.1016/j.neuropharm.2019.108104)

[Niu J, Tsai HH, Hoi KK, et al, Modulation of CSF1R signaling during demyelination (2022)](https://doi.org/10.1038/s41593-022-01163-2)

[Dagher NN, Najafi AR, Kayala KM, et al, Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association (2015)](https://doi.org/10.1038/ncomms8425)

[Mochizuki H, Hosomi N, Fukada S, et al, Hematopoietic stem cell transplantation for CSF1R-related disorder (2023)](https://doi.org/10.1212/WNL.0000000000207534)

Pathway Diagram

The following diagram shows the key molecular relationships involving CSF1R Protein (Colony Stimulating Factor 1 Receptor) discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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CSF1R Protein (Colony Stimulating Factor 1 Receptor)

CSF1R Protein (Colony Stimulating Factor 1 Receptor)

CSF1R Protein (Colony Stimulating Factor 1 Receptor)

Pathway Diagram

Overview

Structure and Domain Architecture

Normal Function in the CNS

Microglial Development and Survival

Signaling Pathways

Microglial Functions

Role in Neurodegeneration

ALSP (CSF1R-Related Disorder)

Alzheimer's Disease

Parkinson's Disease

Multiple Sclerosis

Therapeutic Targeting

CSF1R Inhibitors

Microglial Depletion Strategy

ALSP Treatment

Key Interactions

See Also

References

Pathway Diagram