fip200

fip200

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#f8f9fa;text-align:center;font-size:1.1em;">FIP200</th></tr>
<tr><th>Symbol</th><td>FIP200 (RB1CC1)</td></tr>
<tr><th>Full Name</th><td>Focal Adhesion Kinase Family Interacting Protein of 200kDa</td></tr>
<tr><th>Chromosome</th><td>6q24.2</td></tr>
<tr><th>NCBI Gene ID</th><td>[23226](https://www.ncbi.nlm.nih.gov/gene/23226)</td></tr>
<tr><th>OMIM</th><td>[604709](https://www.omim.org/entry/604709)</td></tr>
<tr><th>Ensembl</th><td>[ENSG00000048991](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000048991)</td></tr>
<tr><th>UniProt</th><td>[Q8WWI1](https://www.uniprot.org/uniprot/Q8WWI1)</td></tr>
<tr><th>Associated Diseases</th><td>[Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), ALS, cancer</td></tr>
</table>
</div>

Overview

fip200

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#f8f9fa;text-align:center;font-size:1.1em;">FIP200</th></tr>
<tr><th>Symbol</th><td>FIP200 (RB1CC1)</td></tr>
<tr><th>Full Name</th><td>Focal Adhesion Kinase Family Interacting Protein of 200kDa</td></tr>
<tr><th>Chromosome</th><td>6q24.2</td></tr>
<tr><th>NCBI Gene ID</th><td>[23226](https://www.ncbi.nlm.nih.gov/gene/23226)</td></tr>
<tr><th>OMIM</th><td>[604709](https://www.omim.org/entry/604709)</td></tr>
<tr><th>Ensembl</th><td>[ENSG00000048991](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000048991)</td></tr>
<tr><th>UniProt</th><td>[Q8WWI1](https://www.uniprot.org/uniprot/Q8WWI1)</td></tr>
<tr><th>Associated Diseases</th><td>[Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), ALS, cancer</td></tr>
</table>
</div>

Overview

FIP200 (also known as RB1CC1 - RB1-Inducible Coiled-Coil 1) is a 200 kDa scaffold protein that plays essential roles in [autophagy](/mechanisms/autophagy) initiation, cell adhesion, migration, and [neuronal survival](/cell-types/neurons). Originally identified as a protein that interacts with focal adhesion kinase (FAK), FIP200 has emerged as a critical regulator of the [ULK1 complex](/mechanisms/ulkl-complex) that initiates autophagosome formation [itakura2008](https://pubmed.ncbi.nlm.nih.gov/18716678/). The dysfunction of FIP200-mediated autophagy is strongly implicated in the pathogenesis of neurodegenerative diseases including [Alzheimer's disease](/diseases/alzheimers-disease) (AD), [Parkinson's disease](/diseases/parkinsons-disease) (PD), and amyotrophic lateral sclerosis (ALS) [comincini2021](https://pubmed.ncbi.nlm.nih.gov/33931024/).

This comprehensive page covers FIP200's molecular functions, its role in neuronal biology, disease associations, signaling pathways, therapeutic implications, and key research findings relevant to neurodegeneration.

Gene and Protein Structure

Gene Organization

The FIP200 gene (RB1CC1) is located on chromosome 6q24.2 and encodes a large protein of 1,664 amino acids with a molecular weight of approximately 200 kDa. The gene contains multiple coiled-coil domains throughout its length, which are critical for protein-protein interactions and complex formation.

Protein Domains

FIP200 possesses several key structural features:

The protein functions primarily as a scaffold, bringing together various signaling components to coordinate cellular responses to nutrient status, growth factor signaling, and cellular stress.[@v2019]

Function in Autophagy

The ULK1 Complex

FIP200 is a core component of the [ULK1 complex](/mechanisms/ulkl-complex), which also includes [ULK1](/genes/ulk1), [ATG13](/genes/atg13), and ATG14L/BARKOR. This complex serves as the master regulator of [autophagy](/mechanisms/autophagy) initiation, acting upstream of the [VPS34](/genes/pik3c3) complex to trigger the nucleation of the phagophore [ganley2011](https://pubmed.ncbi.nlm.nih.gov/21747051/).

The ULK1 complex senses cellular energy status through [AMP-activated protein kinase](/genes/prkaa1) (AMPK) and nutrient availability through [mTOR](/genes/mtor) signaling. When nutrients are plentiful, mTOR phosphorylates and inhibits ULK1. Upon nutrient deprivation, AMPK activates ULK1, which then phosphorylates downstream targets to initiate autophagy [alers2012](https://pubmed.ncbi.nlm.nih.gov/22323402/).

FIP200 within this complex serves as a critical scaffold that:

• Stabilizes the ULK1 complex structure
• Facilitates ULK1 kinase activation
• Links the complex to upstream signaling pathways
• Coordinates the recruitment of downstream autophagy proteins

Autophagy Initiation Mechanism

Under starvation conditions, the ULK1 complex translocates to the [endoplasmic reticulum](/cell-types/neurons) (ER) membrane, where it initiates the formation of the phagophore, the precursor to the autophagosome. FIP200 plays a essential role in this process by:

FIP200 in Neuronal Autophagy

Neurons are particularly dependent on autophagy for protein quality control due to their post-mitotic nature and high metabolic demand. FIP200-mediated autophagy is essential for:

• Mitochondrial quality control: Removing damaged mitochondria through mitophagy
• Protein aggregate clearance: Degrading misfolded proteins and aggregates
• Synaptic maintenance: Regulating synaptic vesicle recycling and neurotransmitter release
• Neuronal survival: Preventing apoptosis under cellular stress

Role in Neurodegenerative Diseases

Alzheimer's Disease

In [Alzheimer's disease](/diseases/alzheimers-disease), FIP200-mediated autophagy is impaired at multiple levels:

The [mTOR signaling](/mechanisms/mtor-signaling-pathway) pathway, which directly regulates FIP200 activity through ULK1 inhibition, is hyperactive in AD brains. This creates a double hit: increased protein synthesis (leading to more amyloidogenic APP processing) combined with decreased autophagy (reducing clearance of toxic species) [mizushima2010](https://pubmed.ncbi.nlm.nih.gov/21801009/).

Parkinson's Disease

In [Parkinson's disease](/diseases/parkinsons-disease), FIP200 plays critical roles in:

Mutations in genes affecting autophagy (including PINK1, PARKIN, and GBA) exacerbate FIP200 dysfunction in PD, creating a vicious cycle of impaired protein clearance and neuronal death.

Amyotrophic Lateral Sclerosis

FIP200 deficiency in microglia promotes ALS progression through:

The [C9orf72](/genes/c9orf72) repeat expansion, the most common genetic cause of ALS and frontotemporal dementia, directly impairs autophagy through altered FIP200 and ULK1 localization [chong2019](https://pubmed.ncbi.nlm.nih.gov/31558759/).

Signaling Pathways

PI3K/AKT/mTOR Pathway

FIP200 participates in key neuronal signaling cascades:

• [PI3K](/genes/pik3r1) pathway: Growth factor activation leads to PI3K/AKT signaling, which activates mTORC1
• [mTOR](/mechanisms/mtor-signaling-pathway) pathway: mTORC1 phosphorylates and inhibits ULK1, blocking autophagy initiation
• AMPK activation: Energy deficit activates AMPK, which directly phosphorylates and activates ULK1

ULK1 Complex Signaling

The ULK1 complex integrates signals from multiple sources:

| Signal | Sensor | Effect on ULK1 Complex |
|--------|--------|------------------------|
| Nutrient deprivation | mTORC1 inhibition | Activation |
| Energy deficit | AMPK | Activation |
| Growth factors | AKT | Inhibition |
| Cellular stress | p38 MAPK | Context-dependent |

Autophagy-Phagy-Endolysosomal Pathway

FIP200-mediated autophagy intersects with other degradation pathways:

The dysfunction of any component disrupts the entire system, leading to accumulation of undegraded material and cellular dysfunction.

Protein Interactions

Core ULK1 Complex Partners

FIP200 directly interacts with:

| Partner | Interaction Type | Function |
|---------|------------------|----------|
| [ULK1](/genes/ulk1) | Direct binding | Kinase substrate, complex scaffold |
| [ULK2](/genes/ulk2) | Direct binding | Redundant kinase function |
| [ATG13](/genes/atg13) | Direct binding | Complex stability |
| ATG14L/BARKOR | Direct binding | ER membrane recruitment |
| [RB1](/genes/rb1) | N-terminal | Transcriptional regulation |

Autophagy Machinery

Extended interacting partners include:

• [VPS34](/genes/pik3c3) (PI3KIII): Lipid kinase generating PI3P for phagophore nucleation
• [BECN1](/genes/becn1): Essential autophagy regulator, part of VPS34 complex
• [ATG14](/genes/atg14): Autophagy-specific PI3K complex component
• [ATG5](/genes/atg5), [ATG7](/genes/atg7), [ATG12](/genes/atg12): Conjugation systems for autophagosome expansion

Signaling Kinases

• [PDK1](/genes/pdk1): Upstream activator of AKT signaling
• [AKT1](/genes/akt1): Growth factor signaling kinase
• [MTOR](/genes/mtor): Central nutrient sensor and autophagy regulator
• [AMPK](/genes/prkaa1): Energy sensor, autophagy activator
• [ULK1](/genes/ulk1), [ULK2](/genes/ulk2): Initiating kinases

Focal Adhesion Proteins

• FAK (PTK2): Original interactor, links to cell adhesion signaling
• [PXN](/genes/pxn) (Paxillin): Scaffold at focal adhesions
• [VCL](/genes/vcl) (Vinculin): Actin binding at adhesion sites

Expression Patterns

Brain Regional Distribution

FIP200 is expressed throughout the [brain](/brain-regions) with highest expression in:

• [Cerebral cortex](/brain-regions/cortex): Particularly Layer 5 pyramidal neurons
• [Hippocampus](/brain-regions/hippocampus): CA1-CA3 regions and dentate gyrus
• [Cerebellum](/brain-regions/cerebellum): Purkinje cells and granule cells
• [Brainstem](/brain-regions/brainstem): Motor and sensory nuclei
• Substantia nigra: Dopaminergic neurons

Cell Type Specificity

Within the brain, FIP200 expression is detected in:

Developmental Expression

FIP200 expression is highest during:

• Embryonic brain development
• Postnatal synaptic maturation
• Periods of active neural circuit formation

Therapeutic Implications

Targeting FIP200 Signaling

Modulating FIP200-mediated autophagy represents a promising therapeutic strategy:

mTOR Inhibitors

• Rapamycin/sirolimus: Allosteric mTORC1 inhibitor, promotes autophagy
• Torin1: ATP-competitive inhibitor, more potent mTORC1/C2 blockade
• Everolimus: FDA-approved for oncology, being explored for neurodegeneration

AMPK Activators

• Metformin: FDA-approved diabetes drug, activates AMPK
• AICAR: AMPK direct agonist
• Berberine: Natural AMPK activator

Direct Autophagy Enhancers

• ULK1 activators: Small molecules promoting ULK1 complex activation
• FIP200 stabilizers: Compounds enhancing FIP200 complex formation
• Autophagy-inducing peptides: Short sequences promoting autophagosome formation

Clinical Considerations

Therapeutic targeting of FIP200 must consider:

Animal Models

Knockout Studies

FIP200 knockout in mice leads to:

• Embryonic lethality: FIP200-/- mice die around E13.5
• Neural tube defects: Abnormal brain development
• Cell proliferation defects: Impaired cell cycle progression
• Autophagy failure: Absence of autophagosome formation

Conditional Knockouts

Neuron-specific FIP200 deletion results in:

• Progressive neurodegeneration: Age-dependent neuron loss
• Motor deficits: Impaired coordination and movement
• Protein aggregate accumulation: Ubiquitin-positive inclusions
• Mitochondrial dysfunction: Altered mitochondrial morphology

Disease Models

In AD mouse models:

• FIP200 overexpression reduces amyloid plaque burden
• Autophagy enhancement improves cognitive function
• mTOR inhibition restores synaptic plasticity

Research Directions

Unresolved Questions

Emerging Areas

See Also

Related Mechanisms

• [Autophagy in Neurodegeneration](/mechanisms/autophagy)
• [ULK1 Complex Pathway](/mechanisms/ulkl-complex)
• [mTOR Signaling Pathway](/mechanisms/mtor-signaling-pathway)
• [PI3K/AKT Signaling](/mechanisms/pi3k-akt-signaling)
• [Lysosomal Function](/mechanisms/lysosomal-dysfunction)
• [Mitophagy in Parkinson's Disease](/mechanisms/mitophagy)

Related Genes

• [ULK1 Gene](/genes/ulk1)
• [ULK2 Gene](/genes/ulk2)
• [ATG13 Gene](/genes/atg13)
• [BECN1 Gene](/genes/becn1)
• [MTOR Gene](/genes/mtor)
• [PRKAA1 Gene](/genes/prkaa1)
• [PIK3C3 Gene](/genes/pik3c3)

Related Diseases

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Amyotrophic Lateral Sclerosis](/diseases/als)
• [Frontotemporal Dementia](/diseases/frontotemporal-dementia)

External Links

• [NCBI Gene: FIP200](https://www.ncbi.nlm.nih.gov/gene/23226)
• [UniProt: Q8WWI1](https://www.uniprot.org/uniprot/Q8WWI1)
• [Ensembl: ENSG00000048991](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000048991)
• [HGNC: RB1CC1](https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:15574)
• [UCSC Genome Browser](https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr6:144900000-146100000)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving fip200 discovered through SciDEX knowledge graph analysis: