DegronMD - Q8NFG4(FLCN)

FUNCTION: Multi-functional protein, involved in both the cellular response to amino acid availability and in the regulation of glycolysis (PubMed:17028174, PubMed:18663353, PubMed:21209915, PubMed:24081491, PubMed:24095279, PubMed:31704029, PubMed:31672913, PubMed:34381247). GTPase-activating protein that plays a key role in the cellular response to amino acid availability through regulation of the mTORC1 signaling cascade controlling the MiT/TFE factors TFEB and TFE3 (PubMed:17028174, PubMed:18663353, PubMed:21209915, PubMed:24081491, PubMed:24095279, PubMed:31704029, PubMed:31672913). Regulates glycolysis by binding to lactate dehydrogenase LDHA, acting as an uncompetitive inhibitor (PubMed:34381247). Activates mTORC1 by acting as a GTPase-activating protein: specifically stimulates GTP hydrolysis by RRAGC/RagC or RRAGD/RagD, promoting the conversion to the GDP-bound state of RRAGC/RagC or RRAGD/RagD, and thereby activating the kinase activity of mTORC1 (PubMed:24095279, PubMed:31704029, PubMed:31672913). The GTPase-activating activity is inhibited during starvation and activated in presence of nutrients (PubMed:31672913). Acts as a key component for mTORC1-dependent control of the MiT/TFE factors TFEB and TFE3, while it is not involved in mTORC1-dependent phosphorylation of canonical RPS6KB1/S6K1 and EIF4EBP1/4E-BP1 (PubMed:21209915, PubMed:24081491, PubMed:31672913). In low-amino acid conditions, the lysosomal folliculin complex (LFC) is formed on the membrane of lysosomes, which inhibits the GTPase-activating activity of FLCN, inactivates mTORC1 and maximizes nuclear translocation of TFEB and TFE3 (PubMed:31672913). Upon amino acid restimulation, RRAGA/RagA (or RRAGB/RagB) nucleotide exchange promotes disassembly of the LFC complex and liberates the GTPase-activating activity of FLCN, leading to activation of mTORC1 and subsequent cytoplasmic retention of TFEB and TFE3 (PubMed:31672913). Indirectly acts as a positive regulator of Wnt signaling by promoting mTOR-dependent cytoplasmic retention of MiT/TFE factor TFE3 (PubMed:31272105). Required for the exit of hematopoietic stem cell from pluripotency by promoting mTOR-dependent cytoplasmic retention of TFE3, thereby increasing Wnt signaling (PubMed:30733432). Acts as an inhibitor of browning of adipose tissue by regulating mTOR-dependent cytoplasmic retention of TFE3 (By similarity). In response to flow stress, regulates STK11/LKB1 accumulation and mTORC1 activation through primary cilia: may act by recruiting STK11/LKB1 to primary cilia for activation of AMPK resided at basal bodies, causing mTORC1 down-regulation (PubMed:27072130). Together with FNIP1 and/or FNIP2, regulates autophagy: following phosphorylation by ULK1, interacts with GABARAP and promotes autophagy (PubMed:25126726). Required for starvation-induced perinuclear clustering of lysosomes by promoting association of RILP with its effector RAB34 (PubMed:27113757). {ECO:0000250|UniProtKB:Q8QZS3, ECO:0000269|PubMed:17028174, ECO:0000269|PubMed:18663353, ECO:0000269|PubMed:21209915, ECO:0000269|PubMed:24081491, ECO:0000269|PubMed:24095279, ECO:0000269|PubMed:25126726, ECO:0000269|PubMed:27072130, ECO:0000269|PubMed:27113757, ECO:0000269|PubMed:30733432, ECO:0000269|PubMed:31272105, ECO:0000269|PubMed:31672913, ECO:0000269|PubMed:31704029, ECO:0000269|PubMed:34381247}. View more >>

GO - Biological processes (BP): cell-cell junction assembly [GO:0007043]; cellular response to amino acid starvation [GO:0034198]; cellular response to starvation [GO:0009267]; energy homeostasis [GO:0097009]; hemopoiesis [GO:0030097]; in utero embryonic development [GO:0001701]; lysosome localization [GO:0032418]; negative regulation of ATP biosynthetic process [GO:2001170]; negative regulation of brown fat cell differentiation [GO:1903444]; negative regulation of cell growth [GO:0030308]; negative regulation of cell migration [GO:0030336]; negative regulation of cell proliferation involved in kidney development [GO:1901723]; negative regulation of cellular respiration [GO:1901856]; negative regulation of cold-induced thermogenesis [GO:0120163]; negative regulation of ERK1 and ERK2 cascade [GO:0070373]; negative regulation of gene expression [GO:0010629]; negative regulation of mitochondrial DNA metabolic process [GO:1901859]; negative regulation of mitochondrion organization [GO:0010823]; negative regulation of muscle tissue development [GO:1901862]; negative regulation of post-translational protein modification [GO:1901874]; negative regulation of protein kinase B signaling [GO:0051898]; negative regulation of protein localization to nucleus [GO:1900181]; negative regulation of Rho protein signal transduction [GO:0035024]; negative regulation of TOR signaling [GO:0032007]; negative regulation of transcription by RNA polymerase II [GO:0000122]; positive regulation of apoptotic process [GO:0043065]; positive regulation of autophagy [GO:0010508]; positive regulation of cell adhesion [GO:0045785]; positive regulation of GTPase activity [GO:0043547]; positive regulation of intrinsic apoptotic signaling pathway [GO:2001244]; positive regulation of protein phosphorylation [GO:0001934]; positive regulation of TORC1 signaling [GO:1904263]; positive regulation of TOR signaling [GO:0032008]; positive regulation of transcription by RNA polymerase II [GO:0045944]; positive regulation of transforming growth factor beta receptor signaling pathway [GO:0030511]; regulation of cytokinesis [GO:0032465]; regulation of histone acetylation [GO:0035065]; regulation of pro-B cell differentiation [GO:2000973]; regulation of protein phosphorylation [GO:0001932]; regulation of Ras protein signal transduction [GO:0046578]; regulation of TOR signaling [GO:0032006]; TOR signaling [GO:0031929] View more >>

GO - Molecular function (MF): View more >>

GO - Cellular component (CC): View more >>

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Mutation	Sample	Cancer	Dataset	Degron hit	Class	Location	Type	Impact score
p.P326Q	TCGA-53-7626	LUAD	TCGA	AESSS	DEG_SPOP_SBC_1	327:331	Mutation rewiring degron network	0.3056
p.P326Q	DO23774	LUAD	ICGC	AESSS	DEG_SPOP_SBC_1	327:331	Mutation rewiring degron network	0.3056
p.S73I	TCGA-55-8511	LUAD	TCGA	VESSS	DEG_SPOP_SBC_1	69:73	Mutation altering degron motif	0.8453
p.S73I	DO24940	LUAD	ICGC	VESSS	DEG_SPOP_SBC_1	69:73	Mutation altering degron motif	0.8453
p.E70K	TCGA-BS-A0UV	UCEC	TCGA	VESSS	DEG_SPOP_SBC_1	69:73	Mutation altering degron motif	0.591
p.E70K	DO42793	UCEC	ICGC	VESSS	DEG_SPOP_SBC_1	69:73	Mutation altering degron motif	0.591
p.E65Q	TCGA-C5-A1M7	CESC	TCGA	VESSS	DEG_SPOP_SBC_1	69:73	Mutation rewiring degron network	0.2222
p.E65Q	DO48981	CESC	ICGC	VESSS	DEG_SPOP_SBC_1	69:73	Mutation rewiring degron network	0.2222
p.S62I	TCGA-DK-AA76	BLCA	TCGA	VESSS	DEG_SPOP_SBC_1	69:73	Mutation blocking phosphorylation signal	0.5833
p.S62I	DO219013	BLCA	ICGC	VESSS	DEG_SPOP_SBC_1	69:73	Mutation blocking phosphorylation signal	0.5833
p.P326S	TCGA-EE-A2GO	SKCM	TCGA	AESSS	DEG_SPOP_SBC_1	327:331	Mutation rewiring degron network	0.3056
p.P326S	DO37823	SKCM	ICGC	AESSS	DEG_SPOP_SBC_1	327:331	Mutation rewiring degron network	0.3056
p.D80N	TCGA-ER-A19W	SKCM	TCGA	VESSS	DEG_SPOP_SBC_1	69:73	Mutation rewiring degron network	0.1389
p.D80N	DO50300	SKCM	ICGC	VESSS	DEG_SPOP_SBC_1	69:73	Mutation rewiring degron network	0.1389
p.S62R	TCGA-OR-A5L3	ACC	TCGA	VESSS	DEG_SPOP_SBC_1	69:73	Mutation blocking phosphorylation signal	0.5833
p.L319P	DO8786	COAD	ICGC	AESSS	DEG_SPOP_SBC_1	327:331	Mutation rewiring degron network	0.1111
p.P326L	DO234199	ESAD	ICGC	AESSS	DEG_SPOP_SBC_1	327:331	Mutation rewiring degron network	0.3056
p.R320K	DO222564	ESCA	ICGC	AESSS	DEG_SPOP_SBC_1	327:331	Mutation rewiring degron network	0.1389
p.A324T	DO233888	GACA	ICGC	AESSS	DEG_SPOP_SBC_1	327:331	Mutation rewiring degron network	0.25
p.A324T	DO42280	UCEC	ICGC	AESSS	DEG_SPOP_SBC_1	327:331	Mutation rewiring degron network	0.25
p.A324T	SIDM01278	Colorectal Carcinoma	GDSC	AESSS	DEG_SPOP_SBC_1	327:331	Mutation rewiring degron network	0.25
p.E321D	DO11016	GBM	ICGC	AESSS	DEG_SPOP_SBC_1	327:331	Mutation rewiring degron network	0.1667
p.E321D	DO47299	SKCM	ICGC	AESSS	DEG_SPOP_SBC_1	327:331	Mutation rewiring degron network	0.1667
p.S341P	DO22237	LGG	ICGC	AESSS	DEG_SPOP_SBC_1	327:331	Mutation rewiring degron network	0.0556
p.P76T	DO229018	LICA	ICGC	VESSS	DEG_SPOP_SBC_1	69:73	Mutation rewiring degron network	0.25
p.A60E	DO229022	LICA	ICGC	VESSS	DEG_SPOP_SBC_1	69:73	Mutation rewiring degron network	0.0833
p.H61R	DO231782	LINC	ICGC	VESSS	DEG_SPOP_SBC_1	69:73	Mutation rewiring degron network	0.1111
p.S318L	DO45526	LUSC	ICGC	AESSS	DEG_SPOP_SBC_1	327:331	Mutation rewiring degron network	0.0833
p.R334W	DO233293	NACA	ICGC	AESSS	DEG_SPOP_SBC_1	327:331	Mutation rewiring degron network	0.25
p.R334W	DO50075	UCEC	ICGC	AESSS	DEG_SPOP_SBC_1	327:331	Mutation rewiring degron network	0.25
p.P338S	DO47368	SKCM	ICGC	AESSS	DEG_SPOP_SBC_1	327:331	Mutation rewiring degron network	0.1389
p.A60V	SIDM00960	Colorectal Carcinoma	GDSC	VESSS	DEG_SPOP_SBC_1	69:73	Mutation rewiring degron network	0.0833
p.A60V	ACH-000798	Colon/Colorectal Cancer	CCLE	VESSS	DEG_SPOP_SBC_1	69:73	Mutation rewiring degron network	0.0833
p.A60V	CL-40	large intestine	COSMIC	VESSS	DEG_SPOP_SBC_1	69:73	Mutation rewiring degron network	0.0833
p.R320W	SIDM01016	T-Lymphoblastic Leukemia	GDSC	AESSS	DEG_SPOP_SBC_1	327:331	Mutation rewiring degron network	0.1389
p.R320W	ACH-000995	Leukemia	CCLE	AESSS	DEG_SPOP_SBC_1	327:331	Mutation rewiring degron network	0.1389
p.R320W	Jurkat	haematopoietic and lymphoid tissue	COSMIC	AESSS	DEG_SPOP_SBC_1	327:331	Mutation rewiring degron network	0.1389
p.S331F	SIDM01038	B-Cell Non-Hodgkin's Lymphoma	GDSC	AESSS	DEG_SPOP_SBC_1	327:331	Mutation altering degron motif	0.7982
p.S331F	JEKO-1	haematopoietic and lymphoid tissue	COSMIC	AESSS	DEG_SPOP_SBC_1	327:331	Mutation altering degron motif	0.7982
p.A64V	SIDM01080	Oral Cavity Carcinoma	GDSC	VESSS	DEG_SPOP_SBC_1	69:73	Mutation rewiring degron network	0.1944
p.A64V	ACH-000181	Head and Neck Cancer	CCLE	VESSS	DEG_SPOP_SBC_1	69:73	Mutation rewiring degron network	0.1944
p.A64V	SCC-9	upper aerodigestive tract	COSMIC	VESSS	DEG_SPOP_SBC_1	69:73	Mutation rewiring degron network	0.1944
p.A67T	SIDM00333	Endometrial Carcinoma	GDSC	VESSS	DEG_SPOP_SBC_1	69:73	Mutation rewiring degron network	0.2778
p.A67T	ACH-000988	Endometrial/Uterine Cancer	CCLE	VESSS	DEG_SPOP_SBC_1	69:73	Mutation rewiring degron network	0.2778
p.A67T	MFE-319	endometrium	COSMIC	VESSS	DEG_SPOP_SBC_1	69:73	Mutation rewiring degron network	0.2778
p.S62G	SIDM00333	Endometrial Carcinoma	GDSC	VESSS	DEG_SPOP_SBC_1	69:73	Mutation blocking phosphorylation signal	0.5833
p.S62G	ACH-000988	Endometrial/Uterine Cancer	CCLE	VESSS	DEG_SPOP_SBC_1	69:73	Mutation blocking phosphorylation signal	0.5833
p.S62G	MFE-319	endometrium	COSMIC	VESSS	DEG_SPOP_SBC_1	69:73	Mutation blocking phosphorylation signal	0.5833
p.R330I	SIDM00402	Bladder Carcinoma	GDSC	AESSS	DEG_SPOP_SBC_1	327:331	Mutation altering degron motif	0.8102
p.R330I	RT-112	urinary tract	COSMIC	AESSS	DEG_SPOP_SBC_1	327:331	Mutation altering degron motif	0.8102
p.T331M	SIDM00849	Kidney Carcinoma	GDSC	AESSS	DEG_SPOP_SBC_1	327:331	Mutation altering degron motif	0.7423
p.P74L	SIDM00217	Colorectal Carcinoma	GDSC	VESSS	DEG_SPOP_SBC_1	69:73	Mutation rewiring degron network	0.3056
p.P74L	ACH-000999	Colon/Colorectal Cancer	CCLE	VESSS	DEG_SPOP_SBC_1	69:73	Mutation rewiring degron network	0.3056
p.P74L	SNU-1040	large intestine	COSMIC	VESSS	DEG_SPOP_SBC_1	69:73	Mutation rewiring degron network	0.3056
p.G334C	ACH-000941	Endometrial/Uterine Cancer	CCLE	AESSS	DEG_SPOP_SBC_1	327:331	Mutation rewiring degron network	0.25

Kaplan plot for FLCN in

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*NOTE: the Kaplan plots were collected from OncoLnc

DegronMD: protein-targeted degradation, mutation and drug response to degrons

FLCN

UniProt ID: Q8NFG4

Entrez ID: 201163

Protein name: Folliculin (BHD skin lesion fibrofolliculoma protein) (Birt-Hogg-Dube syndrome protein)

External links: UniprotKB HGNC RefSeq COSMIC

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Kaplan plot for FLCN in