Affinage

FNIP2

Folliculin-interacting protein 2 · UniProt Q9P278

Length
1114 aa
Mass
122.1 kDa
Annotated
2026-06-09
11 papers in source corpus 9 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FNIP2 is a cytoplasmic scaffold protein that heterodimerizes with folliculin (FLCN) and, through this complex, acts as a positive regulator of mTORC1 signaling at the lysosomal surface (PMID:18403135, PMID:18663353, PMID:31704029). The FLCN-FNIP2 heterodimer adopts an extended conformation in which heterodimerized Longin domains engage both nucleotide-binding domains of the Rag GTPase heterodimer and heterodimerized DENN domains lie at the distal end; a conserved arginine on FLCN serves as the catalytic arginine finger driving GAP activity toward RagC/D, captured structurally as an on-pathway GAP-GTPase intermediate (PMID:31704029). The FLCN-binding interface maps to the C-terminus of both proteins, and FNIP2 can also multimerize with FNIP1; loss of this interaction abolishes FNIP2-mediated cytoplasmic retention of FLCN, defining FNIP2 as a determinant of FLCN subcellular localization (PMID:18403135, PMID:18663353). Beyond mTORC1, FNIP2 operates within an AMPK-FNIP2-FLCN module required for apoptosis induced by O6-methylguanine mismatch, where MLH1-dependent AMPKα phosphorylation after alkylation damage requires FNIP2 and FLCN, and FNIP2 protein is itself post-translationally stabilized in a FLCN-dependent, AMPK-restrained, proteasome-regulated manner during this response (PMID:19137017, PMID:22209521, PMID:23201403). FNIP2 transcription is driven by MEF2A/MEF2D, sustaining mTORC1 lysosomal recruitment in pancreatic cancer (PMID:37772772). A naturally occurring FNIP2 frameshift mutation in Weimaraner dogs causes hypomyelination through failed oligodendrocyte maturation, establishing a developmental requirement for FNIP2 (PMID:24272703). FNIP2 additionally interacts with the SERCA2b calcium channel and modulates calcium availability and mitochondrial metabolism (PMID:41771847).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2008 Medium

    Established FNIP2 as a direct FLCN- and AMPK-binding partner and mapped the interaction to the FLCN C-terminus, linking FNIP2 to the BHD-associated folliculin pathway.

    Evidence Reciprocal Co-IP with FLCN deletion mutants mimicking BHD germline truncations

    PMID:18403135 PMID:18663353

    Open questions at the time
    • Did not define the FNIP2 domains mediating FLCN binding
    • No structural basis for the interaction
  2. 2008 Medium

    Showed FNIP2 controls FLCN subcellular localization and that the complex positively regulates mTORC1, placing FNIP2 within a growth-signaling axis.

    Evidence Fluorescence microscopy with FNIP2 C-terminal truncations and siRNA knockdown with phospho-S6K1 readout

    PMID:18663353

    Open questions at the time
    • Single-lab, single-method KD for the mTORC1 readout
    • Mechanism connecting localization to S6K1 phosphorylation not resolved
  3. 2009 Medium

    Identified FNIP2/MAPO1 as required for O6-methylguanine-induced apoptosis, assigning it a role in the DNA alkylation damage response distinct from mTORC1 regulation.

    Evidence Gene-trap mutagenesis plus siRNA knockdown with sub-G1, caspase-3, and mitochondrial depolarization readouts

    PMID:19137017

    Open questions at the time
    • Did not link the apoptotic role to FLCN at this stage
    • Molecular trigger for FNIP2 engagement in apoptosis unknown
  4. 2011 Medium

    Placed FNIP2 within an AMPK-MAPO1-FLCN module by showing MLH1-dependent AMPKα activation after alkylation damage requires FNIP2 and FLCN.

    Evidence siRNA knockdown with phospho-AMPKα immunoblot and AICAR-induced cell death assays

    PMID:22209521

    Open questions at the time
    • Order of events between MLH1, AMPK, and FNIP2 not fully resolved
    • Whether AMPK directly modifies FNIP2 not addressed
  5. 2012 Medium

    Revealed that FNIP2 protein stability is regulated post-translationally during the damage response, with FLCN promoting and AMPK restraining its accumulation.

    Evidence MG132/cycloheximide treatments and siRNA knockdown with immunoblot stability readouts

    PMID:23201403

    Open questions at the time
    • E3 ligase mediating FNIP2 proteasomal turnover not identified
    • Site of regulatory modification unknown
  6. 2014 Medium

    Demonstrated an in vivo developmental requirement for FNIP2 in oligodendrocyte maturation and myelination via a natural loss-of-function mutation.

    Evidence GWAS, sequencing, and histopathology of FNIP2-frameshift Weimaraner dogs

    PMID:24272703

    Open questions at the time
    • Molecular pathway connecting FNIP2 to oligodendrocyte maturation not defined
    • Whether the phenotype is FLCN/mTORC1-dependent unaddressed
  7. 2019 High

    Provided the structural mechanism for FNIP2 function: the FLCN-FNIP2 heterodimer is a RagC/D GAP using a FLCN arginine finger, defining how the complex activates mTORC1.

    Evidence Cryo-EM of FLCN-FNIP2-Rag-Ragulator with arginine-finger mutagenesis and GTPase assays

    PMID:31704029

    Open questions at the time
    • Functional contribution of the distal DENN domains not fully defined
    • How GAP activity is regulated by upstream signals in cells not addressed
  8. 2023 Medium

    Identified transcriptional control of FNIP2 by MEF2A/MEF2D and showed FNIP2 expression sustains lysosomal mTORC1 activation in cancer.

    Evidence ChIP, luciferase reporters, RT-qPCR, and MEF2D phospho-mutants with mTORC1 readouts in pancreatic cancer cells

    PMID:37772772

    Open questions at the time
    • Generality of MEF2-driven FNIP2 regulation beyond pancreatic cancer untested
    • Direct effect of FNIP2 level on RagC/D GAP activity in this context not measured
  9. 2026 Medium

    Extended FNIP2 function to calcium and metabolic homeostasis via interaction with SERCA2b, with FNIP2 loss rescuing metabolic defects in Ataxia Telangiectasia models.

    Evidence FNIP2-SERCA2b Co-IP plus metabolomics, flux, bioenergetic, and electron tomography analyses in FNIP2-perturbed AT cells

    PMID:41771847

    Open questions at the time
    • Direct vs indirect nature of the SERCA2b interaction not confirmed by reciprocal/structural data
    • Relationship between this calcium role and the FLCN-mTORC1 axis unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How FNIP2's distinct roles—RagC/D GAP/mTORC1 activation, AMPK-coupled damage-induced apoptosis, oligodendrocyte maturation, and SERCA2b-linked calcium/metabolic control—are integrated or differentially deployed in specific cellular contexts remains unresolved.
  • No unified model connecting the mTORC1, apoptotic, myelination, and calcium functions
  • Tissue-specific determinants of which function predominates are unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 1
Localization
GO:0005764 lysosome 2 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 2
Partners
AMPKFLCNFNIP1RAGCRAGDSERCA2B
Complex memberships
AMPK-MAPO1(FNIP2)-FLCN complexFLCN-FNIP2 heterodimerFLCN-FNIP2-Rag-Ragulator complex

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 FNIP2 directly interacts with FLCN (folliculin) and AMPK; C-terminally deleted FLCN mutants (mimicking BHD germline mutations) cannot bind FNIP2, mapping the interaction to the C-terminus of FLCN. FNIP1 and FNIP2 can form homo- or heteromeric multimers with each other. Co-immunoprecipitation, deletion mutant analysis Gene Medium 18403135 18663353
2008 FnipL/FNIP2 retains FLCN in the cytoplasm in a reticular pattern through complex formation; C-terminal truncation of FNIP2 abolishes cytoplasmic retention of FLCN, indicating FNIP2 regulates FLCN subcellular localization. Fluorescence microscopy, siRNA knockdown, C-terminal truncation mutants Oncogene Medium 18663353
2008 Knockdown of FNIP2 (FnipL) by siRNA decreases S6K1 phosphorylation, placing FLCN-FNIP2 complex as a positive regulator of mTORC1-S6K1 signaling. siRNA knockdown, immunoblot for phospho-S6K1 Oncogene Medium 18663353
2009 MAPO1 (FNIP2) is required for apoptosis triggered by O6-methylguanine mismatch; siRNA-mediated knockdown suppresses MNU-induced apoptosis, mitochondrial membrane depolarization, and caspase-3 activation. Both mouse and human MAPO1 proteins localize to the cytoplasm. Retrovirus-mediated gene-trap mutagenesis, siRNA knockdown, flow cytometry (sub-G1), caspase-3 assay, mitochondrial membrane potential assay, immunofluorescence Oncogene Medium 19137017
2011 FNIP2 (MAPO1) functions within the AMPK-MAPO1-FLCN complex in the signaling pathway of apoptosis induced by O6-methylguanine; after MNU exposure, AMPKα phosphorylation is MLH1-dependent and requires MAPO1 and FLCN, as their knockdown abrogates AMPK activation. AICAR-mediated AMPK activation also requires MAPO1 and FLCN and leads to mitochondrial membrane depolarization and cell death. siRNA knockdown, immunoblot (phospho-AMPKα), AICAR treatment, mitochondrial membrane potential assay DNA repair Medium 22209521
2012 FNIP2 (MAPO1) protein is stabilized post-translationally during O6-methylguanine-induced apoptosis via proteasome-mediated regulation: proteasome inhibitor MG132 increases MAPO1 levels; FLCN is required for MAPO1 stability (FLCN knockdown decreases MAPO1 and prevents MNU-induced stabilization); AMPKα keeps MAPO1 destabilized under normal conditions (AMPKα knockdown causes constitutive stabilization); MAPO1 dissociates from AMPK but not FLCN after MNU treatment. Immunoblotting, proteasome inhibitor (MG132), protein synthesis inhibitor (cycloheximide), siRNA knockdown Biochemical and biophysical research communications Medium 23201403
2014 A frameshift mutation in FNIP2 in Weimaraner dogs causes hypomyelination and tract-specific myelin defects in the spinal cord, with failure of maturation of a subpopulation of oligodendrocytes, establishing FNIP2 as required for oligodendrocyte maturation and myelination. Genome-wide association study, sequencing, histopathology, immunohistochemistry Glia Medium 24272703
2019 Cryo-EM structure of the FLCN-FNIP2-Rag-Ragulator complex reveals: FLCN-FNIP2 adopts an extended conformation with heterodimerized Longin domains contacting both nucleotide-binding domains of the Rag heterodimer, and heterodimerized DENN domains at the distal end. A conserved arginine on FLCN acts as the catalytic arginine finger for GAP activity toward RagC/D, and the structure represents an on-pathway GAP-GTPase intermediate. Cryo-EM structure determination, biochemical mutagenesis (arginine finger mutant), GTPase activity assay Cell High 31704029
2023 Transcription factors MEF2A and MEF2D directly regulate FNIP2 transcription; SRC kinase phosphorylates MEF2D at three conserved tyrosine residues to enhance its transcriptional activity and thus FNIP2 expression, which sustains mTORC1 recruitment to lysosomes and activation in pancreatic cancer. ChIP, RT-qPCR, luciferase reporter assay, immunoblot, siRNA knockdown, phosphomimetic/unphosphorylatable MEF2D mutants Autophagy Medium 37772772
2026 FNIP2 interacts with the SERCA2b calcium channel; inactivation of FNIP2 in Ataxia Telangiectasia (AT) cellular models enhances cytoplasmic calcium availability, stimulates mitochondrial respiration, increases glucose consumption, prevents glycogen accumulation, and improves cell survival, partially rescuing AT metabolic defects. Co-immunoprecipitation (FNIP2-SERCA2b), metabolomics, flux analysis, bioenergetic measurements, electron tomography, FNIP2 knockdown/knockout in AT cells Cell death & disease Medium 41771847
2024 MITF activates expression of FNIP2 (along with FNIP1 and FLCN), and the resulting FLCN-FNIP2 complex promotes cytoplasmic retention and lysosome-mediated degradation of TFE3 in melanoma, suppressing the mesenchymal/invasive state. Gene expression analysis, TFE3 deletion, FNIP2/FNIP1/FLCN overexpression, migration and metastasis assays bioRxivpreprint Low

Source papers

Stage 0 corpus · 11 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Identification and characterization of a novel folliculin-interacting protein FNIP2. Gene 148 18403135
2019 Cryo-EM Structure of the Human FLCN-FNIP2-Rag-Ragulator Complex. Cell 109 31704029
2008 Interaction of folliculin (Birt-Hogg-Dubé gene product) with a novel Fnip1-like (FnipL/Fnip2) protein. Oncogene 107 18663353
2021 Whole Transcriptome Analysis Reveals a Potential Regulatory Mechanism of LncRNA-FNIP2/miR-24-3p/FNIP2 Axis in Chicken Adipogenesis. Frontiers in cell and developmental biology 22 34249911
2011 Activation of AMP-activated protein kinase by MAPO1 and FLCN induces apoptosis triggered by alkylated base mismatch in DNA. DNA repair 18 22209521
2023 Direct regulation of FNIP1 and FNIP2 by MEF2 sustains MTORC1 activation and tumor progression in pancreatic cancer. Autophagy 13 37772772
2014 A mutation in the canine gene encoding folliculin-interacting protein 2 (FNIP2) associated with a unique disruption in spinal cord myelination. Glia 9 24272703
2009 A novel protein, MAPO1, that functions in apoptosis triggered by O6-methylguanine mispair in DNA. Oncogene 9 19137017
2022 Folliculin-interacting protein FNIP2 impacts on overweight and obesity through a polymorphism in a conserved 3' untranslated region. Genome biology 5 36316722
2012 Stabilization of MAPO1 by specific binding with folliculin and AMP-activated protein kinase in O⁶-methylguanine-induced apoptosis. Biochemical and biophysical research communications 4 23201403
2026 Targeting the FNIP2-SERCA2b axis improves metabolic and mitochondrial defects in Ataxia Telangiectasia. Cell death & disease 0 41771847

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