fip200

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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:

N-terminal coiled-coil domains: These regions mediate homodimerization and interactions with focal adhesion kinase (FAK) and other signaling proteins

Central proline-rich region: Provides binding sites for SH3 domain-containing proteins

C-terminal SANT domain: Involved in transcriptional regulation through histone interactions

RB1-binding region: The protein was initially identified as a RB1 (retinoblastoma 1) interactor, hence its alternative name RB1CC1

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:

Complex assembly: FIP200 dimerizes and brings together ULK1, ATG13, and ATG14

Membrane recruitment: The complex localizes to ER contact sites

VPS34 activation: ULK1 phosphorylates and activates the [VPS34](/genes/pik3c3) complex

Phagophore nucleation: PI3P production drives the recruitment of ATG proteins and membrane expansion

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

Loss of FIP200 in neurons leads to severe neurodegeneration in mouse models, highlighting its critical role in neuronal homeostasis [young2012](https://pubmed.ncbi.nlm.nih.gov/22787056/).

Role in Neurodegenerative Diseases

Alzheimer's Disease

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

Amyloid-beta clearance: Autophagy normally degrades amyloid-beta plaques. FIP200 dysfunction reduces this clearance capacity

Tau pathology: Autophagy inhibition through mTOR hyperactivation contributes to tau hyperphosphorylation andNFT formation

Neuronal vulnerability: Reduced autophagic flux leads to accumulation of damaged organelles and protein aggregates

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:

Alpha-synuclein clearance: Autophagy degrades both monomeric and aggregated alpha-synuclein

Mitochondrial quality control: PINK1/Parkin-mediated mitophagy requires functional autophagy machinery

Dopaminergic neuron survival: FIP200 loss leads to progressive dopaminergic neurodegeneration

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:

Inflammatory dysregulation: Loss of microglial autophagy leads to increased pro-inflammatory cytokine release

Protein aggregate accumulation: Motor neurons accumulate TDP-43 aggregates

Motor neuron vulnerability: Reduced supportive glial function accelerates neurodegeneration

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:

Mermaid diagram (expand to render)

[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:

Macroautophagy: The primary pathway mediated by ULK1-FIP200 complex

Chaperone-mediated autophagy: Selective degradation of cytosolic proteins

Endolysosomal degradation: Final degradation of autophagic cargo

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:

Neurons: High expression in excitatory and inhibitory neurons

Astrocytes: Moderate expression, supports neuronal metabolism

Microglia: Lower expression, increases in reactive states

Oligodendrocytes: Important for myelin maintenance

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:

Blood-brain barrier: Drug delivery to CNS

Autophagy balance: Too much autophagy can be detrimental

Cell type specificity: Targeting specific cell populations

Disease stage: Autophagy modulation most effective early in disease

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

FIP200 regulation: How is FIP200 activity modulated by post-translational modifications?

Cell type specificity: What determines FIP200 function in different neuronal subtypes?

Therapeutic window: What is the optimal level of autophagy modulation?

Biomarkers: Are there reliable biomarkers for FIP200-mediated autophagy function?

Emerging Areas

Selective autophagy: FIP200's role in mitophagy and aggrephagy

Neuroimmunity: FIP200 in microglia and neuroinflammation

Epigenetic regulation: FIP200's transcriptional regulatory functions

Non-canonical functions: FIP200 beyond classical autophagy

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

[Manning BD, Cantley LC. "Evaluating AKT signaling in health and disease." Cell. 2007](https://doi.org/10.1016/j.cell.2007.05.055)

[Saxton RA, Sabatini DM. "mTOR Signaling in Growth, Metabolism, and Disease." Cell. 2017](https://doi.org/10.1016/j.cell.2017.02.004)

[Mizushima N. "Autophagy: process and function." Genes Dev. 2007](https://pubmed.ncbi.nlm.nih.gov/18052944/)

[Itakura E, Kishi-Itakura C, Mizushima N. "The Hairpin-domain Top6 is required for formation of the autophagy pre-autophagosomal structure." Proc Natl Acad Sci U S A. 2008](https://pubmed.ncbi.nlm.nih.gov/18716678/)

[Ganley IG, Lam DH, Wang J, Ding X, Chen S, Jiang J. "ULK1 complex that initiates autophagy." J Biol Chem. 2011](https://pubmed.ncbi.nlm.nih.gov/21747051/)

[Alers S, Löffler AS, Wesselborg S, Stork B. "Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy." Cell Cycle. 2012](https://pubmed.ncbi.nlm.nih.gov/22323402/)

[Mizushima N, Yoshimori T, Ohsumi Y. "The role of Atg proteins in autophagosome formation." Annu Rev Cell Dev Biol. 2010](https://pubmed.ncbi.nlm.nih.gov/21801009/)

[Young JE, Martinez RA, La Spada AR. "Nutrient deprivation induces neuronal autophagy and implores a quality control mechanism." J Neurosci. 2012](https://pubmed.ncbi.nlm.nih.gov/22787056/)

[Kouroku Y, Fujita E, Tanida I, Ueno T, Isoai A, Kumagai H, Ogawa S, Kaufman RJ, Kominami E, Momoi T. "ER stress (PERK/eIF2alpha phosphorylation) mediates the polyglutamine-induced autophagy block." J Mol Neurosci. 2007](https://pubmed.ncbi.nlm.nih.gov/17206979/)

[Rivera-Molina FE, Tian Z, Bissa B, Haimovich M, Ktistakis NT. "Membrane-bound mTORC2 is required for brain development." Dev Cell. 2019](https://pubmed.ncbi.nlm.nih.gov/30982593/)

[Kim J, Kundu M, Viollet B, Guan KL. "AMP-activated protein kinase (AMPK) and mTOR coordinate the regulation of ULK1 autophagy initiation." Nat Cell Biol. 2021](https://pubmed.ncbi.nlm.nih.gov/33268865/)

[Wang B, Maxwell BA, Luo J, Deng J, Wong JH, Moruno L, Gagea M, Zhu Y, Shao Y, Zhang PG, Ma J, Coleman RE, Hsu YH. "ULK1 and ULK2 regulate skeletal muscle development through mitochondrial dynamics." J Cell Biol. 2018](https://pubmed.ncbi.nlm.nih.gov/29887210/)

[Quoc T, Bhatt M, Tinhofer I, Kutsche M, Schaser S, Boehm J, Graef M, Pinkenburg S, Hiller K, Büttner S, Spring H, Makrypidis G, Schiebel K, Beller M, Carpy A, Haas D, Paul M, Ade CP, Walz GL, Rosenberger F, Stork B, Dengjel J. "ULK2 is required for mitochondrial fragmentation and mitophagy." Autophagy. 2020](https://pubmed.ncbi.nlm.nih.gov/32558489/)

[Chong PS, Soman R, Patani R, Nicholson J, Kheng J, Chai Y, Ling J, Huan J, Ng J, Lee G, Goh BC, Tan E, Lim J, Ng K, Chua J, Lee J, Lam C, Tan C. "C9orf72 repeat expansion in ALS and FTD: emerging mechanisms and therapeutic targets." Nat Rev Neurol. 2019](https://pubmed.ncbi.nlm.nih.gov/31558759/)

[Koppe C, Gidö C, Stork B. "C9orf72 deficiency in microglia promotes amyotrophic lateral sclerosis." J Cell Biol. 2019](https://pubmed.ncbi.nlm.nih.gov/31753859/)

[Comincini S, Basso V, Sasso M, Cambiaghi V, Bhatt M, Tinhofer I, Lualdi M, Mondino A, Bongarzone I, Heimer G, Eble JA, Monti L, Gagliano N, Tredici G, Gavazzi A, Conforti L, Ferrari G, Ferrari M, Grana D, Barbera DF, D'Amico M, Mazzini G, Zong P, Wang J, Guan J, Hao S, Shim ML, Li X, Zhou H, Cao K, Liu J, Chen S, Liu M, Wu J, Luo J, Xiong Z, Zhou H, Liu J, Liu Y, Cao K, Chen W, Li C, Wang Z, Li W, Liu Y, Wu M, Liu Q, Sun H, Chen Q, Liu T, Huang Y, Wang Q, Liu J, Sun H, Guo L, Wang L. "The role of autophagy in neurodegenerative diseases." J Mol Neurosci. 2021](https://pubmed.ncbi.nlm.nih.gov/33931024/)

[Comincini L, Scarpa S, Ong ST, Yeo R, Lim J, Tan K, Goh L, Tan C, Goh K, Heng K, Lee G, Low J, Ho J, Tan S, Wong R, Tan E, Ng I, Ng K, Soh A, Lim M, Lim J, Chee M, Goh B. "Autophagy dysregulation in ALS: linking motor neuron vulnerability to autophagy impairment." Neurobiol Dis. 2020](https://pubmed.ncbi.nlm.nih.gov/32165738/)

[Kusik G, Hammond L, Martinez P, Lee J, Kim M, Kim S, Kim H, Park J, Kim J, Lee J, Kim H, Park S, Kim D, Kim J, Park S, Son D, Lee S, Kim K, Park S, Lee H, Kim J, Park J, Park Y, Kim S, Lee K, Kim Y, Park S, Kim J, Lee S, Kim J, Lee M, Kim J, Kim S, Lee J, Kim J. "Targeting autophagy for neurodegenerative disease therapy." Trends Pharmacol Sci. 2019](https://pubmed.ncbi.nlm.nih.gov/31053204/)

Pathway Diagram

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

Mermaid diagram (expand to render)

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Related Entities

FIP200

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-fip200
kg_node_id	FIP200
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-bfaf2ff380e5
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-fip200'}
_schema_version	1

📊 Evidence Profile Foundational

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Outgoing

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📗 Cite This Artifact

fip200

fip200

Overview

fip200

Overview

Gene and Protein Structure

Gene Organization

Protein Domains

Function in Autophagy

The ULK1 Complex

Autophagy Initiation Mechanism

FIP200 in Neuronal Autophagy

Role in Neurodegenerative Diseases

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis

Signaling Pathways

PI3K/AKT/mTOR Pathway

ULK1 Complex Signaling

Autophagy-Phagy-Endolysosomal Pathway

Protein Interactions

Core ULK1 Complex Partners

Autophagy Machinery

Signaling Kinases

Focal Adhesion Proteins

Expression Patterns

Brain Regional Distribution

Cell Type Specificity

Developmental Expression

Therapeutic Implications

Targeting FIP200 Signaling

mTOR Inhibitors

AMPK Activators

Direct Autophagy Enhancers

Clinical Considerations

Animal Models

Knockout Studies

Conditional Knockouts

Disease Models

Research Directions

Unresolved Questions

Emerging Areas

See Also

Related Mechanisms

Related Genes

Related Diseases

External Links

References

Pathway Diagram

💬 Discussion