ID FNIP1_HUMAN Reviewed; 1166 AA. AC Q8TF40; D6RJH5; Q86T47; Q9BUT0; DT 23-OCT-2007, integrated into UniProtKB/Swiss-Prot. DT 30-NOV-2010, sequence version 3. DT 27-MAR-2024, entry version 144. DE RecName: Full=Folliculin-interacting protein 1 {ECO:0000303|PubMed:17028174}; GN Name=FNIP1 {ECO:0000303|PubMed:17028174, ECO:0000312|HGNC:HGNC:29418}; GN Synonyms=KIAA1961 {ECO:0000303|PubMed:11853319}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, INTERACTION WITH FLCN; HSPCA; PRKAA1; RP PRKAB1 AND PRKAG1, PHOSPHORYLATION, TISSUE SPECIFICITY, IDENTIFICATION BY RP MASS SPECTROMETRY, AND VARIANTS CYS-76 AND ARG-648. RX PubMed=17028174; DOI=10.1073/pnas.0603781103; RA Baba M., Hong S.-B., Sharma N., Warren M.B., Nickerson M.L., Iwamatsu A., RA Esposito D., Gillette W.K., Hopkins R.F. III, Hartley J.L., Furihata M., RA Oishi S., Zhen W., Burke T.R. Jr., Linehan W.M., Schmidt L.S., Zbar B.; RT "Folliculin encoded by the BHD gene interacts with a binding protein, RT FNIP1, and AMPK, and is involved in AMPK and mTOR signaling."; RL Proc. Natl. Acad. Sci. U.S.A. 103:15552-15557(2006). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15372022; DOI=10.1038/nature02919; RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S., RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M., RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S., RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M., RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M., RA Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T., RA Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., RA Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R., RA Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L., RA Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N., RA Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., RA Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., RA Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.; RT "The DNA sequence and comparative analysis of human chromosome 5."; RL Nature 431:268-274(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT CYS-76. RC TISSUE=Lung; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 196-1166 (ISOFORM 3), AND VARIANT RP ARG-648. RC TISSUE=Brain; RX PubMed=11853319; DOI=10.1093/dnares/8.6.319; RA Nagase T., Kikuno R., Ohara O.; RT "Prediction of the coding sequences of unidentified human genes. XXII. The RT complete sequences of 50 new cDNA clones which code for large proteins."; RL DNA Res. 8:319-327(2001). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 617-1166, AND VARIANT ARG-648. RC TISSUE=Skeletal muscle; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [6] RP SUBUNIT, AND TISSUE SPECIFICITY. RX PubMed=18403135; DOI=10.1016/j.gene.2008.02.022; RA Hasumi H., Baba M., Hong S.-B., Hasumi Y., Huang Y., Yao M., Valera V.A., RA Linehan W.M., Schmidt L.S.; RT "Identification and characterization of a novel folliculin-interacting RT protein FNIP2."; RL Gene 415:60-67(2008). RN [7] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=18663353; DOI=10.1038/onc.2008.261; RA Takagi Y., Kobayashi T., Shiono M., Wang L., Piao X., Sun G., Zhang D., RA Abe M., Hagiwara Y., Takahashi K., Hino O.; RT "Interaction of folliculin (Birt-Hogg-Dube gene product) with a novel RT Fnip1-like (FnipL/Fnip2) protein."; RL Oncogene 27:5339-5347(2008). RN [8] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-593; SER-594; SER-760 AND RP SER-763, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [9] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-760 AND SER-763, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [10] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-760 AND SER-763, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [11] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=24081491; DOI=10.1083/jcb.201307084; RA Petit C.S., Roczniak-Ferguson A., Ferguson S.M.; RT "Recruitment of folliculin to lysosomes supports the amino acid-dependent RT activation of Rag GTPases."; RL J. Cell Biol. 202:1107-1122(2013). RN [12] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-220; THR-294 AND SER-296, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [13] RP FUNCTION. RX PubMed=25126726; DOI=10.4161/auto.29640; RA Dunlop E.A., Seifan S., Claessens T., Behrends C., Kamps M.A., Rozycka E., RA Kemp A.J., Nookala R.K., Blenis J., Coull B.J., Murray J.T., RA van Steensel M.A., Wilkinson S., Tee A.R.; RT "FLCN, a novel autophagy component, interacts with GABARAP and is regulated RT by ULK1 phosphorylation."; RL Autophagy 10:1749-1760(2014). RN [14] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-220, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [15] RP FUNCTION, SUBUNIT, INTERACTION WITH HSP70; HSP90AA1; FLCN; STIP1; PTGES3; RP CDC37; BRAF; GCR AND CDK4, AND TISSUE SPECIFICITY. RX PubMed=27353360; DOI=10.1038/ncomms12037; RA Woodford M.R., Dunn D.M., Blanden A.R., Capriotti D., Loiselle D., RA Prodromou C., Panaretou B., Hughes P.F., Smith A., Ackerman W., RA Haystead T.A., Loh S.N., Bourboulia D., Schmidt L.S., Marston Linehan W., RA Bratslavsky G., Mollapour M.; RT "The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance RT drug binding."; RL Nat. Commun. 7:12037-12037(2016). RN [16] RP SUBCELLULAR LOCATION. RX PubMed=29848618; DOI=10.1083/jcb.201712177; RA Meng J., Ferguson S.M.; RT "GATOR1-dependent recruitment of FLCN-FNIP to lysosomes coordinates Rag RT GTPase heterodimer nucleotide status in response to amino acids."; RL J. Cell Biol. 217:2765-2776(2018). RN [17] RP FUNCTION, INTERACTION WITH HSP90AA1, PHOSPHORYLATION AT SER-938; SER-939; RP SER-941; SER-946 AND SER-948, GLYCOSYLATION AT SER-938, UBIQUITINATION AT RP LYS-1119, AND MUTAGENESIS OF 938-SER--SER-948; SER-938; LYS-982; LYS-1117; RP LYS-1119 AND LYS-1134. RX PubMed=30699359; DOI=10.1016/j.celrep.2019.01.018; RA Sager R.A., Woodford M.R., Backe S.J., Makedon A.M., Baker-Williams A.J., RA DiGregorio B.T., Loiselle D.R., Haystead T.A., Zachara N.E., Prodromou C., RA Bourboulia D., Schmidt L.S., Linehan W.M., Bratslavsky G., Mollapour M.; RT "Post-translational regulation of FNIP1 creates a rheostat for the RT molecular chaperone Hsp90."; RL Cell Rep. 26:1344-1356(2019). RN [18] RP FUNCTION, PHOSPHORYLATION AT SER-220; SER-230; SER-232; SER-261 AND RP SER-593, AND MUTAGENESIS OF SER-220; 230-SER--SER-232; SER-261 AND SER-593. RX PubMed=37079666; DOI=10.1126/science.abj5559; RA Malik N., Ferreira B.I., Hollstein P.E., Curtis S.D., Trefts E., RA Weiser Novak S., Yu J., Gilson R., Hellberg K., Fang L., Sheridan A., RA Hah N., Shadel G.S., Manor U., Shaw R.J.; RT "Induction of lysosomal and mitochondrial biogenesis by AMPK RT phosphorylation of FNIP1."; RL Science 380:eabj5559-eabj5559(2023). RN [19] RP VARIANT IMD93 ASN-1118, TISSUE SPECIFICITY, AND INVOLVEMENT IN IMD93. RX PubMed=32181500; DOI=10.1002/eji.201948504; RA Niehues T., Oezguer T.T., Bickes M., Waldmann R., Schoening J., Braesen J., RA Hagel C., Ballmaier M., Klusmann J.H., Niedermayer A., Pannicke U., RA Enders A., Dueckers G., Siepermann K., Hempel J., Schwarz K., Viemann D.; RT "Mutations of the gene FNIP1 associated with a syndromic autosomal RT recessive immunodeficiency with cardiomyopathy and pre-excitation RT syndrome."; RL Eur. J. Immunol. 50:1078-1080(2020). RN [20] RP VARIANT IMD93 290-ARG--LEU-1166 DEL, INVOLVEMENT IN IMD93, AND FUNCTION. RX PubMed=32905580; DOI=10.1182/blood.2020006441; RA Saettini F., Poli C., Vengoechea J., Bonanomi S., Orellana J.C., Fazio G., RA Rodriguez F.H., Noguera L.P., Booth C., Jarur-Chamy V., Shams M., RA Iascone M., Vukic M., Gasperini S., Quadri M., Barroeta Seijas A., RA Rivers E., Mauri M., Badolato R., Cazzaniga G., Bugarin C., Gaipa G., RA Kroes W.G.M., Moratto D., van Oostaijen-Ten Dam M.M., Baas F., RA van der Maarel S., Piazza R., Coban-Akdemir Z.H., Lupski J.R., Yuan B., RA Chinn I.K., Daxinger L., Biondi A.; RT "Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in RT folliculin-interacting protein 1 deficiency."; RL Blood 137:493-499(2021). CC -!- FUNCTION: Binding partner of the GTPase-activating protein FLCN: CC involved in the cellular response to amino acid availability by CC regulating the non-canonical mTORC1 signaling cascade controlling the CC MiT/TFE factors TFEB and TFE3 (PubMed:17028174, PubMed:18663353, CC PubMed:24081491, PubMed:37079666). Required to promote FLCN recruitment CC to lysosomes and interaction with Rag GTPases, leading to activation of CC the non-canonical mTORC1 signaling (PubMed:24081491). In low-amino acid CC conditions, component of the lysosomal folliculin complex (LFC) on the CC membrane of lysosomes, which inhibits the GTPase-activating activity of CC FLCN, thereby inactivating mTORC1 and promoting nuclear translocation CC of TFEB and TFE3 (By similarity). Upon amino acid restimulation, CC disassembly of the LFC complex liberates the GTPase-activating activity CC of FLCN, leading to activation of mTORC1 and subsequent inactivation of CC TFEB and TFE3 (PubMed:37079666). Together with FLCN, regulates CC autophagy: following phosphorylation by ULK1, interacts with GABARAP CC and promotes autophagy (PubMed:25126726). In addition to its role in CC mTORC1 signaling, also acts as a co-chaperone of HSP90AA1/Hsp90: CC following gradual phosphorylation by CK2, inhibits the ATPase activity CC of HSP90AA1/Hsp90, leading to activate both kinase and non-kinase CC client proteins of HSP90AA1/Hsp90 (PubMed:27353360, PubMed:30699359). CC Acts as a scaffold to load client protein FLCN onto HSP90AA1/Hsp90 CC (PubMed:27353360). Competes with the activating co-chaperone AHSA1 for CC binding to HSP90AA1, thereby providing a reciprocal regulatory CC mechanism for chaperoning of client proteins (PubMed:27353360). Also CC acts as a core component of the reductive stress response by inhibiting CC activation of mitochondria in normal conditions: in response to CC reductive stress, the conserved Cys degron is reduced, leading to CC recognition and polyubiquitylation by the CRL2(FEM1B) complex, followed CC by proteasomal (By similarity). Required for B-cell development CC (PubMed:32905580). {ECO:0000250|UniProtKB:Q68FD7, CC ECO:0000250|UniProtKB:Q9P278, ECO:0000269|PubMed:17028174, CC ECO:0000269|PubMed:18663353, ECO:0000269|PubMed:24081491, CC ECO:0000269|PubMed:25126726, ECO:0000269|PubMed:27353360, CC ECO:0000269|PubMed:30699359, ECO:0000269|PubMed:32905580, CC ECO:0000269|PubMed:37079666}. CC -!- SUBUNIT: Homodimer and homomultimer (PubMed:18403135, PubMed:27353360). CC Heterodimer and heteromultimer with FNIP2 (PubMed:18403135, CC PubMed:27353360). Interacts with FLCN (via C-terminus) CC (PubMed:17028174, PubMed:27353360). Component of the lysosomal CC folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), CC RagA/RRAGA or RagB/RRAGB GDP-bound, RagC/RRAGC or RagD/RRAGD GTP-bound, CC and Ragulator (By similarity). Interacts with HSPCA and with the CC PRKAA1, PRKAB1 and PRKAG1 subunits of 5'-AMP-activated protein kinase CC (AMPK) (PubMed:17028174). Phosphorylated FLCN and AMPK are CC preferentially bound (PubMed:17028174). Interacts with HSP70, STIP1, CC PTGES3, CDC37, BRAF, GCR and CDK4 (PubMed:27353360). Interacts with CC HSP90AA1; the interaction inhibits HSP90AA1 ATPase activity CC (PubMed:27353360, PubMed:30699359). Interacts with ATP2A2 (By CC similarity). {ECO:0000250|UniProtKB:Q68FD7, CC ECO:0000250|UniProtKB:Q9P278, ECO:0000269|PubMed:17028174, CC ECO:0000269|PubMed:18403135, ECO:0000269|PubMed:27353360, CC ECO:0000269|PubMed:30699359}. CC -!- INTERACTION: CC Q8TF40; Q8NFG4: FLCN; NbExp=5; IntAct=EBI-2946919, EBI-2970160; CC Q8TF40; Q9P278: FNIP2; NbExp=7; IntAct=EBI-2946919, EBI-7597109; CC Q8TF40; O95166: GABARAP; NbExp=5; IntAct=EBI-2946919, EBI-712001; CC Q8TF40; Q9H0R8: GABARAPL1; NbExp=2; IntAct=EBI-2946919, EBI-746969; CC Q8TF40; Q9Q2G4: ORF; Xeno; NbExp=3; IntAct=EBI-2946919, EBI-6248094; CC Q8TF40-1; Q8NFG4-1: FLCN; NbExp=7; IntAct=EBI-15604805, EBI-15604776; CC -!- SUBCELLULAR LOCATION: Lysosome membrane {ECO:0000269|PubMed:29848618}. CC Cytoplasm, cytosol {ECO:0000269|PubMed:18663353, CC ECO:0000269|PubMed:29848618}. Note=Localizes to lysosome membrane in CC amino acid-depleted conditions and relocalizes to the cytosol upon CC refeeding (PubMed:29848618). Colocalizes with FLCN in the cytoplasm CC (PubMed:18663353). {ECO:0000269|PubMed:18663353, CC ECO:0000269|PubMed:29848618}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q8TF40-1; Sequence=Displayed; CC Name=2; CC IsoId=Q8TF40-2; Sequence=VSP_028982, VSP_028983; CC Name=3; CC IsoId=Q8TF40-3; Sequence=VSP_028984; CC -!- TISSUE SPECIFICITY: Strong expression is found in the heart, liver CC placenta, muscle, nasal mucosa, salivary gland and uvula and moderate CC expression in kidney and lung. Higher levels detected in clear cell CC renal cell carcinoma (RCC) and chromophobe RCC than in normal kidney CC tissue. Expressed in peripheral blood mononuclear cells CC (PubMed:32181500). {ECO:0000269|PubMed:17028174, CC ECO:0000269|PubMed:18403135, ECO:0000269|PubMed:27353360, CC ECO:0000269|PubMed:32181500}. CC -!- DOMAIN: The KY-finger orients the Cys degron for ubiquitination by the CC CRL2(FEM1B) complex. {ECO:0000250|UniProtKB:Q68FD7}. CC -!- PTM: Phosphorylated by AMPK in response to energetic stress CC (PubMed:17028174, PubMed:37079666). Phosphorylation by AMPK in response CC to mitochondrial damage promotes inactivation of the non-canonical CC mTORC1 signaling, nuclear translocation of TFEB and TFE3, inducing CC transcription of lysosomal or autophagy genes (PubMed:37079666). CC Sequential phosphorylation by CK2 promotes its gradual interaction with CC HSP90AA1/Hsp90 (PubMed:30699359). Priming phosphorylation at Ser-938 is CC followed by relay phosphorylation at Ser-939, Ser-941, Ser-946 and Ser- CC 948, promoting its gradual interaction with HSP90AA1/Hsp90 CC (PubMed:30699359). This leads to incremental inhibition of CC HSP90AA1/Hsp90 ATPase activity and gradual activation of both kinase CC and non-kinase clients (PubMed:30699359). Dephosphorylated by protein CC phosphatase 5 (PP5), promoting glycosylation by OGT (PubMed:30699359). CC {ECO:0000269|PubMed:17028174, ECO:0000269|PubMed:30699359, CC ECO:0000269|PubMed:37079666}. CC -!- PTM: GlcNAcylation at Ser-938 by OGT following dephosphorylation by CC protein phosphatase 5 (PP5) promotes ubiquitination and degradation by CC the proteasome. {ECO:0000269|PubMed:30699359}. CC -!- PTM: Ubiquitinated through 'Lys-11' linkage of ubiquitin moieties at CC Lys-1119 following glycosylation by OGT, leading to its degradation by CC the proteasome (PubMed:30699359). Ubiquitinated by the CRL2(FEM1B) CC complex in response to reductive stress: reductive stress causes CC reduction of the conserved Cys degron in FNIP1, followed by zinc- CC binding, zinc acting as a molecular glue for recognition by the CC CRL2(FEM1B) complex (By similarity). Ubiquitination leads to FNIP1 CC degradation, and activation of mitochondria to recalibrate reactive CC oxygen species (ROS) (By similarity). {ECO:0000250|UniProtKB:Q68FD7, CC ECO:0000269|PubMed:30699359}. CC -!- PTM: Oxidation of the Cys degron in normal conditions promotes its CC stabilization by preventing recognition and ubiquitination by the CC CRL2(FEM1B) complex. {ECO:0000250|UniProtKB:Q68FD7}. CC -!- DISEASE: Immunodeficiency 93 and hypertrophic cardiomyopathy (IMD93) CC [MIM:619705]: An autosomal recessive disorder characterized by onset of CC recurrent viral and bacterial infections, particularly with CC encapsulated bacteria, and hypertrophic cardiomyopathy in the first CC months or years of life. {ECO:0000269|PubMed:32181500, CC ECO:0000269|PubMed:32905580}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the FNIP family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/44003/FNIP1"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; DQ145719; AAZ65854.1; -; mRNA. DR EMBL; AC004227; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC004622; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC005593; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC008695; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC008497; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC026754; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC001956; AAH01956.1; -; mRNA. DR EMBL; AB075841; BAB85547.1; -; mRNA. DR EMBL; AL832008; CAD91145.1; -; mRNA. DR CCDS; CCDS34226.1; -. [Q8TF40-3] DR CCDS; CCDS34227.1; -. [Q8TF40-1] DR CCDS; CCDS87321.1; -. [Q8TF40-2] DR RefSeq; NP_001008738.2; NM_001008738.2. [Q8TF40-3] DR RefSeq; NP_001333042.1; NM_001346113.1. [Q8TF40-2] DR RefSeq; NP_588613.2; NM_133372.2. [Q8TF40-1] DR AlphaFoldDB; Q8TF40; -. DR BioGRID; 125175; 41. DR ComplexPortal; CPX-2624; FLCN-FNIP GTPase-activating complex, FNIP1 variant. DR DIP; DIP-57169N; -. DR IntAct; Q8TF40; 15. DR MINT; Q8TF40; -. DR STRING; 9606.ENSP00000421985; -. DR GlyCosmos; Q8TF40; 1 site, 1 glycan. DR GlyGen; Q8TF40; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q8TF40; -. DR PhosphoSitePlus; Q8TF40; -. DR BioMuta; FNIP1; -. DR DMDM; 313104236; -. DR EPD; Q8TF40; -. DR jPOST; Q8TF40; -. DR MassIVE; Q8TF40; -. DR MaxQB; Q8TF40; -. DR PaxDb; 9606-ENSP00000421985; -. DR PeptideAtlas; Q8TF40; -. DR ProteomicsDB; 74549; -. [Q8TF40-1] DR ProteomicsDB; 74550; -. [Q8TF40-2] DR ProteomicsDB; 74551; -. [Q8TF40-3] DR Pumba; Q8TF40; -. DR Antibodypedia; 25902; 168 antibodies from 25 providers. DR DNASU; 96459; -. DR Ensembl; ENST00000307968.11; ENSP00000309266.7; ENSG00000217128.13. [Q8TF40-3] DR Ensembl; ENST00000510461.6; ENSP00000421985.1; ENSG00000217128.13. [Q8TF40-1] DR Ensembl; ENST00000511848.1; ENSP00000425619.1; ENSG00000217128.13. [Q8TF40-2] DR GeneID; 96459; -. DR KEGG; hsa:96459; -. DR MANE-Select; ENST00000510461.6; ENSP00000421985.1; NM_133372.3; NP_588613.3. DR UCSC; uc003kvs.2; human. [Q8TF40-1] DR AGR; HGNC:29418; -. DR CTD; 96459; -. DR DisGeNET; 96459; -. DR GeneCards; FNIP1; -. DR HGNC; HGNC:29418; FNIP1. DR HPA; ENSG00000217128; Low tissue specificity. DR MalaCards; FNIP1; -. DR MIM; 610594; gene. DR MIM; 619705; phenotype. DR neXtProt; NX_Q8TF40; -. DR OpenTargets; ENSG00000217128; -. DR PharmGKB; PA142671758; -. DR VEuPathDB; HostDB:ENSG00000217128; -. DR eggNOG; KOG3693; Eukaryota. DR GeneTree; ENSGT00390000009391; -. DR HOGENOM; CLU_026421_0_0_1; -. DR InParanoid; Q8TF40; -. DR OMA; AWHSTQQ; -. DR OrthoDB; 2725349at2759; -. DR PhylomeDB; Q8TF40; -. DR TreeFam; TF324090; -. DR PathwayCommons; Q8TF40; -. DR Reactome; R-HSA-9639288; Amino acids regulate mTORC1. DR SignaLink; Q8TF40; -. DR SIGNOR; Q8TF40; -. DR BioGRID-ORCS; 96459; 29 hits in 1162 CRISPR screens. DR ChiTaRS; FNIP1; human. DR GenomeRNAi; 96459; -. DR Pharos; Q8TF40; Tbio. DR PRO; PR:Q8TF40; -. DR Proteomes; UP000005640; Chromosome 5. DR RNAct; Q8TF40; Protein. DR Bgee; ENSG00000217128; Expressed in cardiac muscle of right atrium and 199 other cell types or tissues. DR ExpressionAtlas; Q8TF40; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB. DR GO; GO:0042030; F:ATPase inhibitor activity; IDA:UniProtKB. DR GO; GO:0008047; F:enzyme activator activity; IDA:UniProt. DR GO; GO:0019899; F:enzyme binding; IPI:UniProtKB. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0051087; F:protein-folding chaperone binding; IDA:UniProtKB. DR GO; GO:0001783; P:B cell apoptotic process; IEA:Ensembl. DR GO; GO:0030183; P:B cell differentiation; IMP:UniProtKB. DR GO; GO:0009267; P:cellular response to starvation; ISS:UniProtKB. DR GO; GO:0002327; P:immature B cell differentiation; ISS:UniProtKB. DR GO; GO:0008285; P:negative regulation of cell population proliferation; IEA:Ensembl. DR GO; GO:0043154; P:negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; ISS:UniProtKB. DR GO; GO:1905672; P:negative regulation of lysosome organization; IDA:UniProtKB. DR GO; GO:0032007; P:negative regulation of TOR signaling; ISS:UniProtKB. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:UniProtKB. DR GO; GO:0002904; P:positive regulation of B cell apoptotic process; ISS:UniProtKB. DR GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; IDA:UniProtKB. DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IMP:UniProtKB. DR GO; GO:0031334; P:positive regulation of protein-containing complex assembly; IDA:ParkinsonsUK-UCL. DR GO; GO:0032008; P:positive regulation of TOR signaling; IDA:UniProtKB. DR GO; GO:1904263; P:positive regulation of TORC1 signaling; IDA:UniProtKB. DR GO; GO:2000973; P:regulation of pro-B cell differentiation; ISS:UniProtKB. DR GO; GO:0001932; P:regulation of protein phosphorylation; IDA:UniProtKB. DR GO; GO:0031929; P:TOR signaling; IMP:UniProtKB. DR InterPro; IPR037545; DENN_FNIP1/2. DR InterPro; IPR028086; FNIP_C_dom. DR InterPro; IPR026156; FNIP_fam. DR InterPro; IPR028085; FNIP_mid_dom. DR InterPro; IPR028084; FNIP_N_dom. DR PANTHER; PTHR21634:SF12; FOLLICULIN-INTERACTING PROTEIN 1; 1. DR PANTHER; PTHR21634; UNCHARACTERIZED; 1. DR Pfam; PF14638; FNIP_C; 1. DR Pfam; PF14637; FNIP_M; 1. DR Pfam; PF14636; FNIP_N; 1. DR PRINTS; PR02073; FOLLICULNIP1. DR PROSITE; PS51836; DENN_FNIP12; 1. DR Genevisible; Q8TF40; HS. PE 1: Evidence at protein level; KW Alternative splicing; Cardiomyopathy; Cytoplasm; Disease variant; KW Glycoprotein; Isopeptide bond; Lysosome; Membrane; Metal-binding; KW Oxidation; Phosphoprotein; Reference proteome; Ubl conjugation; Zinc. FT CHAIN 1..1166 FT /note="Folliculin-interacting protein 1" FT /id="PRO_0000308484" FT DOMAIN 37..478 FT /note="uDENN FNIP1/2-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01180" FT DOMAIN 486..1092 FT /note="cDENN FNIP1/2-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01180" FT DOMAIN 1102..1157 FT /note="dDENN FNIP1/2-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01180" FT REGION 611..612 FT /note="KY-finger" FT /evidence="ECO:0000250|UniProtKB:Q68FD7" FT REGION 781..817 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 912..956 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 929..1166 FT /note="Interaction with HSP90AA1" FT /evidence="ECO:0000269|PubMed:27353360" FT MOTIF 608..615 FT /note="Cys degron" FT /evidence="ECO:0000250|UniProtKB:Q68FD7" FT COMPBIAS 781..803 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 912..930 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 608 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /ligand_note="ligand shared with FEM1B" FT /evidence="ECO:0000250|UniProtKB:Q68FD7" FT BINDING 610 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /ligand_note="ligand shared with FEM1B" FT /evidence="ECO:0000250|UniProtKB:Q68FD7" FT BINDING 613 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /ligand_note="ligand shared with FEM1B" FT /evidence="ECO:0000250|UniProtKB:Q68FD7" FT BINDING 613 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /ligand_note="ligand shared with FEM1B" FT /evidence="ECO:0000250|UniProtKB:Q68FD7" FT BINDING 615 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /ligand_note="ligand shared with FEM1B" FT /evidence="ECO:0000250|UniProtKB:Q68FD7" FT MOD_RES 220 FT /note="Phosphoserine; by AMPK" FT /evidence="ECO:0000269|PubMed:37079666, FT ECO:0007744|PubMed:23186163, ECO:0007744|PubMed:24275569" FT MOD_RES 230 FT /note="Phosphoserine; by AMPK" FT /evidence="ECO:0000269|PubMed:37079666" FT MOD_RES 232 FT /note="Phosphoserine; by AMPK" FT /evidence="ECO:0000269|PubMed:37079666" FT MOD_RES 261 FT /note="Phosphoserine; by AMPK" FT /evidence="ECO:0000269|PubMed:37079666" FT MOD_RES 294 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 296 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 593 FT /note="Phosphoserine; by AMPK" FT /evidence="ECO:0000269|PubMed:37079666, FT ECO:0007744|PubMed:18669648" FT MOD_RES 594 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 760 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231" FT MOD_RES 763 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231" FT MOD_RES 938 FT /note="Phosphoserine; alternate; by CK2" FT /evidence="ECO:0000269|PubMed:30699359" FT MOD_RES 939 FT /note="Phosphoserine; by CK2" FT /evidence="ECO:0000269|PubMed:30699359" FT MOD_RES 941 FT /note="Phosphoserine; by CK2" FT /evidence="ECO:0000269|PubMed:30699359" FT MOD_RES 946 FT /note="Phosphoserine; by CK2" FT /evidence="ECO:0000269|PubMed:30699359" FT MOD_RES 948 FT /note="Phosphoserine; by CK2" FT /evidence="ECO:0000269|PubMed:30699359" FT CARBOHYD 938 FT /note="O-linked (GlcNAc) serine; alternate" FT /evidence="ECO:0000269|PubMed:30699359" FT CROSSLNK 1119 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:30699359" FT VAR_SEQ 208..235 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:11853319" FT /id="VSP_028984" FT VAR_SEQ 508 FT /note="D -> M (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_028982" FT VAR_SEQ 509..1166 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_028983" FT VARIANT 76 FT /note="G -> C (in dbSNP:rs7730228)" FT /evidence="ECO:0000269|PubMed:15489334, FT ECO:0000269|PubMed:17028174" FT /id="VAR_036824" FT VARIANT 290..1166 FT /note="Missing (in IMD93; undetectable protein in FT homozygous patient cells)" FT /evidence="ECO:0000269|PubMed:32905580" FT /id="VAR_086807" FT VARIANT 354 FT /note="S -> L (in dbSNP:rs13177318)" FT /id="VAR_036825" FT VARIANT 648 FT /note="Q -> R (in dbSNP:rs26008)" FT /evidence="ECO:0000269|PubMed:11853319, FT ECO:0000269|PubMed:17028174, ECO:0000269|PubMed:17974005" FT /id="VAR_036826" FT VARIANT 738 FT /note="V -> L (in dbSNP:rs12109782)" FT /id="VAR_036827" FT VARIANT 844 FT /note="I -> V (in dbSNP:rs7717874)" FT /id="VAR_036828" FT VARIANT 1118 FT /note="S -> N (in IMD93; uncertain significance)" FT /evidence="ECO:0000269|PubMed:32181500" FT /id="VAR_086808" FT MUTAGEN 220 FT /note="S->A: In SA5 mutant; Abolishes phosphorylation by FT AMPK, leading to activation of the non-canonical mTORC1 FT signaling; when associated with 230-A--A-232, A-261 and FT A-593." FT /evidence="ECO:0000269|PubMed:37079666" FT MUTAGEN 230..232 FT /note="SAS->AAA: In SA5 mutant; Abolishes phosphorylation FT by AMPK, leading to activation of the non-canonical mTORC1 FT signaling; when associated with A-220, A-261 and A-593." FT /evidence="ECO:0000269|PubMed:37079666" FT MUTAGEN 261 FT /note="S->A: In SA5 mutant; Abolishes phosphorylation by FT AMPK, leading to activation of the non-canonical mTORC1 FT signaling; when associated with A-220, 230-A--A-232 and FT A-593." FT /evidence="ECO:0000269|PubMed:37079666" FT MUTAGEN 593 FT /note="S->A: In SA5 mutant; Abolishes phosphorylation by FT AMPK, leading to activation of the non-canonical mTORC1 FT signaling; when associated with A-220, 230-A--A-232 and FT A-261." FT /evidence="ECO:0000269|PubMed:37079666" FT MUTAGEN 938..948 FT /note="SSDSALGDSES->EDEALGDEEE: Mimics phosphorylation FT status; leading to inhibit ATPase activity of FT HSP90AA1/Hsp90." FT /evidence="ECO:0000269|PubMed:30699359" FT MUTAGEN 938 FT /note="S->A: Impaired phosphorylation by CK2 and FT interaction with HSP90AA1/Hsp90." FT /evidence="ECO:0000269|PubMed:30699359" FT MUTAGEN 982 FT /note="K->R: No effect on ubiquitination and protein FT stability." FT /evidence="ECO:0000269|PubMed:30699359" FT MUTAGEN 1117 FT /note="K->R: No effect on ubiquitination and protein FT stability." FT /evidence="ECO:0000269|PubMed:30699359" FT MUTAGEN 1119 FT /note="K->R: Impaired ubiquitination, leading to increased FT stability." FT /evidence="ECO:0000269|PubMed:30699359" FT MUTAGEN 1134 FT /note="K->R: No effect on ubiquitination and protein FT stability." FT /evidence="ECO:0000269|PubMed:30699359" SQ SEQUENCE 1166 AA; 130555 MW; 3B99DBA98E7169C5 CRC64; MAPTLFQKLF SKRTGLGAPG RDARDPDCGF SWPLPEFDPS QIRLIVYQDC ERRGRNVLFD SSVKRRNEDI SVSKLGSDAQ VKVFGKCCQL KPGGDSSSSL DSSVTSSSDI KDQCLKYQGS RCSSDANMLG EMMFGSVAMS YKGSTLKIHQ IRSPPQLMLS KVFTARTGSS ICGSLNTLQD SLEFINQDNN TLKADNNTVI NGLLGNIGLS QFCSPRRAFS EQGPLRLIRS ASFFAVHSNP MDMPGRELNE DRDSGIARSA SLSSLLITPF PSPNSSLTRS CASSYQRRWR RSQTTSLENG VFPRWSIEES FNLSDESCGP NPGIVRKKKI AIGVIFSLSK DEDENNKFNE FFFSHFPLFE SHMNKLKSAI EQAMKMSRRS ADASQRSLAY NRIVDALNEF RTTICNLYTM PRIGEPVWLT MMSGTPEKNH LCYRFMKEFT FLMENASKNQ FLPALITAVL TNHLAWVPTV MPNGQPPIKI FLEKHSSQSV DMLAKTHPYN PLWAQLGDLY GAIGSPVRLA RTVVVGKRQD MVQRLLYFLT YFIRCSELQE THLLENGEDE AIVMPGTVIT TTLEKGEIEE SEYVLVTMHR NKSSLLFKES EEIRTPNCNC KYCSHPLLGQ NVENISQQER EDIQNSSKEL LGISDECQMI SPSDCQEENA VDVKQYRDKL RTCFDAKLET VVCTGSVPVD KCALSESGLE STEETWQSEK LLDSDSHTGK AMRSTGMVVE KKPPDKIVPA SFSCEAAQTK VTFLIGDSMS PDSDTELRSQ AVVDQITRHH TKPLKEERGA IDQHQETKQT TKDQSGESDT QNMVSEEPCE LPCWNHSDPE SMSLFDEYFN DDSIETRTID DVPFKTSTDS KDHCCMLEFS KILCTKNNKQ NNEFCKCIET VPQDSCKTCF PQQDQRDTLS ILVPHGDKES SDKKIAVGTE WDIPRNESSD SALGDSESED TGHDMTRQVS SYYGGEQEDW AEEDEIPFPG SKLIEVSAVQ PNIANFGRSL LGGYCSSYVP DFVLQGIGSD ERFRQCLMSD LSHAVQHPVL DEPIAEAVCI IADMDKWTVQ VASSQRRVTD NKLGKEVLVS SLVSNLLHST LQLYKHNLSP NFCVMHLEDR LQELYFKSKM LSEYLRGQMR VHVKELGVVL GIESSDLPLL AAVASTHSPY VAQILL //