| 2006 |
FNIP1 physically interacts with folliculin (FLCN) and with AMP-activated protein kinase (AMPK); FNIP1 is phosphorylated by AMPK, and AMPK inhibitors reduce FNIP1 phosphorylation and expression; FLCN phosphorylation is diminished by rapamycin and amino acid starvation and facilitated by FNIP1 overexpression, placing FNIP1 in AMPK and mTOR signaling. |
Co-immunoprecipitation, in vitro/cell-based phosphorylation assays, AMPK inhibitor treatment, rapamycin treatment, FNIP1 overexpression |
Proceedings of the National Academy of Sciences of the United States of America |
High |
17028174
|
| 2008 |
FNIP1 interacts with FLCN primarily through C-terminal domains of each protein; FNIP1 knockdown decreases S6K1 phosphorylation, indicating the FLCN-FNIP1 complex positively regulates mTOR/S6K1 signaling; FLCN localization shifts from nuclear to cytoplasmic when co-expressed with FNIP1/FNIP2. |
Co-immunoprecipitation, siRNA knockdown, S6K1 phosphorylation assay, subcellular localization by imaging |
Oncogene |
Medium |
18663353
|
| 2012 |
Fnip1 deletion in mice causes a complete block in B cell development at the pre-B cell stage; AMPK and mTOR are dysregulated in Fnip1-null pre-B cells, causing excessive cell growth and enhanced apoptosis sensitivity; an immunoglobulin transgene fails to rescue the block, indicating the arrest is metabolic rather than antigen-receptor-dependent. |
Chemical mutagenesis, Fnip1 knockout mice, flow cytometry, immunoglobulin transgene rescue, AMPK/mTOR activity assays |
Immunity |
High |
22608497
|
| 2012 |
Conditional deletion of Flcn in mice recapitulates the pro-B cell developmental arrest seen in Fnip1-null mice; the block is rescued by a Bcl2 transgene preventing caspase-induced cell death; the B cell arrest operates through both mTOR-dependent and mTOR-independent pathways. |
Conditional knockout mice, Bcl2 transgene rescue, flow cytometry, caspase activity assays |
Blood |
High |
22709692
|
| 2014 |
Fnip1 null mice show increased type I slow-twitch muscle fibers with elevated AMPK activation and PGC1α expression; genetic disruption of PGC1α in Fnip1-null mice rescues normal levels of type I fiber markers (MyH7, myoglobin), placing FNIP1 upstream of AMPK-PGC1α in fiber type specification; loss of Fnip1 mitigates muscle damage in mdx muscular dystrophy mice. |
Fnip1 knockout mice, double KO with PGC1α, fiber type immunostaining, mitochondrial assays, metabolomics, mdx cross |
Proceedings of the National Academy of Sciences of the United States of America |
High |
25548157
|
| 2014 |
Fnip1 is required for iNKT cell development; Fnip1-null iNKT cells show hyperactive mTOR and reduced mitochondrial number despite lower ATP, leading to apoptosis; transcription factor PLZF fails to downregulate normally, and loss of Bim does not rescue the developmental arrest. |
Fnip1 knockout mice, flow cytometry for iNKT stages, mTOR activity assays, mitochondrial staining, Bim-null cross, PLZF analysis |
Proceedings of the National Academy of Sciences of the United States of America |
High |
24785297
|
| 2015 |
Crystal structure of the N-terminal region of the yeast FNIP1/2 orthologue Lst4 confirms it contains a longin domain (first domain of the DENN module); recombinant Lst7/Lst4 complex exists as a 1:1 heterodimer; Lst4 interacts with Lst7 (yeast FLCN orthologue) through its DENN domain; the Lst7/Lst4 complex relocates to the vacuolar membrane during nutrient (carbon) starvation. |
X-ray crystallography, size-exclusion chromatography, Co-IP, live-cell imaging of vacuolar relocalization |
Open biology |
High |
26631379
|
| 2016 |
miR-499 directly targets the 3′UTR of Fnip1 mRNA; Fnip1 inhibits AMPK, which in turn activates PGC-1α-dependent mitochondrial oxidative program; inhibition of Fnip1 reactivates AMPK/PGC-1α signaling and restores mitochondrial function in myocytes, establishing a miR-499/Fnip1/AMPK circuit coupling muscle fiber type to mitochondrial function. |
In vivo miR-499 overexpression in mice, Fnip1 3′UTR luciferase reporter, Fnip1 siRNA in myocytes, AMPK/PGC-1α activity assays, fiber type analysis |
EMBO molecular medicine |
High |
27506764
|
| 2016 |
A recessive loss-of-function Fnip1 variant in mice causes profound B cell deficiency (partially restored by BCL2 overexpression), cardiomyopathy with left ventricular hypertrophy and glycogen accumulation, elevated γ2-specific AMPK activity in neonatal myocardium, and increased AMPK-dependent ULK1 phosphorylation and autophagy in B cell progenitors, supporting FNIP1 as a negative regulator of AMPK. |
ENU mutagenesis, Fnip1 knockin mice, BCL2 transgene rescue, AMPK subunit-specific activity assays, ULK1 phosphorylation assay, cardiac histology |
Proceedings of the National Academy of Sciences of the United States of America |
High |
27303042
|
| 2018 |
Loss of Fnip1 in mice is sufficient to cause renal cyst formation associated with decreased AMPK activation, increased mTOR activation, and metabolic hyperactivation; Fnip1 loss synergizes with Tsc1 loss to hyperactivate mTOR and ERK and greatly accelerate polycystic kidney disease. |
Constitutive Fnip1 knockout mice, Tsc1/Fnip1 double knockout, AMPK/mTOR/ERK phosphorylation assays, RNAseq, histology |
PloS one |
High |
29897930
|
| 2019 |
Casein kinase 2 (CK2) phosphorylates FNIP1 at a priming serine-938, followed by relay phosphorylation on S939, S941, S946, and S948, promoting FNIP1 interaction with Hsp90 and incremental inhibition of Hsp90 ATPase activity leading to gradual activation of Hsp90 clients; PP5 phosphatase dephosphorylates FNIP1, enabling O-GlcNAc addition to S938 that prevents Hsp90 interaction and promotes K1119 ubiquitination and proteasomal degradation of FNIP1. |
In vitro kinase assays, site-directed mutagenesis, Co-IP, Hsp90 ATPase assay, O-GlcNAc modification assays, ubiquitination assay, proteasome inhibitor treatment |
Cell reports |
High |
30699359
|
| 2021 |
In skeletal muscle, FNIP1 inhibits AMPK to suppress mitochondrial oxidative program; basal FNIP1 levels are sufficient to inhibit AMPK but not mTORC1; FNIP1 control of mitochondrial program is AMPK-dependent, whereas FNIP1 control of type I fiber program is independent of AMPK and its downstream target PGC-1α. |
Fnip1 transgenic and knockout mice, Fnip1TgKO double model (muscle-specific rescue), AMPK/mTORC1 activity assays, primary muscle cell culture, fiber type analysis |
PLoS genetics |
High |
33780446
|
| 2021 |
Loss of FLCN or its binding partners FNIP1/FNIP2 in human renal tubular epithelial cells induces an interferon response gene program independently of interferon, promoting STAT2 recruitment to chromatin and slowing cellular proliferation; TFE3 is activated by FLCN loss, upregulating RRAGD and GPNMB without modifying mTORC1 activity. |
CRISPR/Cas9 knockout of FLCN, FNIP1, FNIP2 in RPTEC/TERT1 cells, transcriptomics, ChIP for STAT2, proliferation assays, mTORC1 activity measurement |
eLife |
High |
33459596
|
| 2022 |
FNIP1 binds to and promotes activity of SERCA (sarco/endoplasmic reticulum Ca2+-ATPase), the main Ca2+ pump for cytosolic Ca2+ removal; adipocyte-specific ablation of FNIP1 results in enhanced intracellular Ca2+ signals, activating a Ca2+-dependent thermogenic program (increased UCP1, mitochondrial content, respiration) and protecting against high-fat diet-induced insulin resistance. |
Adipocyte-specific Fnip1 knockout mice, Co-IP of FNIP1 with SERCA, Ca2+ imaging, mitochondrial respiration assays, SERCA activity assay, UCP1 measurement |
The Journal of experimental medicine |
High |
35412553
|
| 2023 |
AMPK directly phosphorylates five conserved serine residues in FNIP1, suppressing FLCN-FNIP1 complex function; this FNIP1 phosphorylation is required for AMPK to induce nuclear translocation of TFEB and TFEB-dependent increases of PGC1α and ERRα mRNAs, thereby driving lysosomal and then mitochondrial biogenesis in response to mitochondrial damage. |
In vitro AMPK kinase assay with FNIP1 mutants, site-directed mutagenesis of five serine residues, TFEB nuclear translocation imaging, gene expression analysis, AMPK activator/inhibitor treatments |
Science (New York, N.Y.) |
High |
37079666
|
| 2023 |
MEF2A and MEF2D transcription factors directly regulate FNIP1 and FNIP2 transcription; SRC kinase phosphorylates MEF2D at three conserved tyrosines to enhance its transcriptional activity, increasing FNIP1/FNIP2 expression; the FLCN-FNIP1/2 complex acts as a RRAGC/D GTPase-activating element to promote mTORC1 lysosomal recruitment and activation in pancreatic cancer. |
Luciferase reporter assay (MEF2 binding to FNIP1/2 promoters), ChIP, MEF2D mutagenesis, SRC kinase assay, mTORC1 lysosomal fractionation, MEF2A/D double depletion |
Autophagy |
High |
37772772
|
| 2023 |
Myofiber-specific FNIP1 deficiency induces PGC-1α to activate chemokine gene transcription, driving macrophage recruitment and a functional angiogenesis program in skeletal muscle; the increased angiogenesis is independent of AMPK; exercise downregulates muscle FNIP1 expression. |
Myofiber-specific Fnip1 knockout and overexpression mice, hindlimb ischemia model, macrophage depletion, PGC-1α ChIP for chemokine promoters, flow cytometry, blood flow measurement |
Nature communications |
High |
37932296
|
| 2024 |
AMPK phosphorylation of FNIP1 at serine-220 (S220) controls mitochondrial electron transfer chain complex assembly, fuel utilization, and exercise endurance in skeletal muscle; S220A (non-phosphorylatable) and S220D (phosphomimic) transgenic models demonstrate that this specific phosphorylation site regulates mitochondrial function without affecting mTORC1-TFEB signaling. |
AMPK in vitro kinase assay on FNIP1-S220, S220A and S220D transgenic mice, mitochondrial ETC complex assembly assay, exercise performance testing, primary muscle cell biochemical analysis |
Science advances |
High |
38324677
|
| 2024 |
Muscle-specific FNIP1 deficiency stimulates nuclear translocation of TFEB, which activates transcription of Igf2 at a conserved promoter-binding site; muscle-derived IGF2 is secreted and stimulates osteoclastogenesis through IGF2 receptor signaling, causing bone loss; this defines a FNIP1-TFEB-IGF2 muscle-bone cross-talk axis. |
Muscle-specific Fnip1 KO and OE mice, ChIP for TFEB at Igf2 promoter, AAV9-IGF2 overexpression, osteoclast assays, bone micro-CT, serum IGF2 measurement |
Science translational medicine |
High |
38838134
|
| 2024 |
FNIP1 binds phosphorylated STAT3 (p-STAT3) and suppresses its expression; FNIP1 deletion increases STAT3 phosphorylation and nuclear localization, promoting colorectal cancer progression; p-STAT3 inhibitors rescue the excessive tumorigenesis caused by FNIP1 absence. |
Co-IP of FNIP1 with p-STAT3, FNIP1 knockout/knockdown in CRC cells, in vivo xenograft, STAT3 nuclear localization assay, chemical inhibitor rescue |
iScience |
Medium |
39262790
|
| 2024 |
In melanoma, MITF suppresses the mesenchymal phenotype by activating expression of FNIP1, FNIP2, and FLCN, which encode components of the non-canonical mTORC1 pathway; these components promote cytoplasmic retention and lysosome-mediated degradation of TFE3, thereby suppressing the mesenchymal/invasive state. |
MITF ChIP/transcriptional activation assays, TFE3 deletion in MITF-low cell lines, migration/metastasis assays, FNIP1/FLCN overexpression, lysosomal degradation assays |
bioRxivpreprint |
Medium |
bio_10.1101_2024.07.11.603140
|
| 2026 |
In Fnip1 conditional knockout mice, loss of Fnip1 in transitional B cells arrests development at the B220+CD93mid stage by dysregulating BCR signaling thresholds through the AMPK/FLCN/TFEB and CD19/PI3K/Akt/mTORC1 pathways; FNIP1 restricts TFEB nuclear access, and its loss accumulates CD19high RAG-negative B cells; FNIP1 is required for peripheral tolerance maintenance but dispensable for negative selection. |
Conditional Fnip1 knockout mice, flow cytometry, BCR signaling assays, MD4/mHEL/sHEL tolerance model, TFEB nuclear localization assay, PI3K/Akt/mTORC1 activity measurement |
bioRxivpreprint |
Medium |
41959523
|