DegronMD - P42345(MTOR)

FUNCTION: Serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals (PubMed:12087098, PubMed:12150925, PubMed:12150926, PubMed:12231510, PubMed:12718876, PubMed:14651849, PubMed:15268862, PubMed:15467718, PubMed:15545625, PubMed:15718470, PubMed:18497260, PubMed:18762023, PubMed:18925875, PubMed:20516213, PubMed:20537536, PubMed:21659604, PubMed:23429703, PubMed:23429704, PubMed:25799227, PubMed:26018084). MTOR directly or indirectly regulates the phosphorylation of at least 800 proteins. Functions as part of 2 structurally and functionally distinct signaling complexes mTORC1 and mTORC2 (mTOR complex 1 and 2) (PubMed:15268862, PubMed:15467718, PubMed:18925875, PubMed:18497260, PubMed:20516213, PubMed:21576368, PubMed:21659604, PubMed:23429704). Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis (PubMed:12087098, PubMed:12150925, PubMed:12150926, PubMed:12231510, PubMed:12718876, PubMed:14651849, PubMed:15268862, PubMed:15467718, PubMed:15545625, PubMed:15718470, PubMed:18497260, PubMed:18762023, PubMed:18925875, PubMed:20516213, PubMed:20537536, PubMed:21659604, PubMed:23429703, PubMed:23429704, PubMed:25799227, PubMed:26018084). This includes phosphorylation of EIF4EBP1 and release of its inhibition toward the elongation initiation factor 4E (eiF4E) (By similarity). Moreover, phosphorylates and activates RPS6KB1 and RPS6KB2 that promote protein synthesis by modulating the activity of their downstream targets including ribosomal protein S6, eukaryotic translation initiation factor EIF4B, and the inhibitor of translation initiation PDCD4 (PubMed:12150925, PubMed:12087098, PubMed:18925875). This also includes mTORC1 signaling cascade controlling the MiT/TFE factors TFEB and TFE3: in the presence of nutrients, mediates phosphorylation of TFEB and TFE3, promoting their cytosolic retention and inactivation (PubMed:22576015, PubMed:22343943, PubMed:22692423). Upon starvation or lysosomal stress, inhibition of mTORC1 induces dephosphorylation and nuclear translocation of TFEB and TFE3, promoting their transcription factor activity (PubMed:22576015, PubMed:22343943, PubMed:22692423). Stimulates the pyrimidine biosynthesis pathway, both by acute regulation through RPS6KB1-mediated phosphorylation of the biosynthetic enzyme CAD, and delayed regulation, through transcriptional enhancement of the pentose phosphate pathway which produces 5-phosphoribosyl-1-pyrophosphate (PRPP), an allosteric activator of CAD at a later step in synthesis, this function is dependent on the mTORC1 complex (PubMed:23429704, PubMed:23429703). Regulates ribosome synthesis by activating RNA polymerase III-dependent transcription through phosphorylation and inhibition of MAF1 an RNA polymerase III-repressor (PubMed:20516213). In parallel to protein synthesis, also regulates lipid synthesis through SREBF1/SREBP1 and LPIN1 (By similarity). To maintain energy homeostasis mTORC1 may also regulate mitochondrial biogenesis through regulation of PPARGC1A (By similarity). mTORC1 also negatively regulates autophagy through phosphorylation of ULK1 (By similarity). Under nutrient sufficiency, phosphorylates ULK1 at 'Ser-758', disrupting the interaction with AMPK and preventing activation of ULK1 (By similarity). Also prevents autophagy through phosphorylation of the autophagy inhibitor DAP (PubMed:20537536). Also prevents autophagy by phosphorylating RUBCNL/Pacer under nutrient-rich conditions (PubMed:30704899). Prevents autophagy by mediating phosphorylation of AMBRA1, thereby inhibiting AMBRA1 ability to mediate ubiquitination of ULK1 and interaction between AMBRA1 and PPP2CA (PubMed:23524951, PubMed:25438055). mTORC1 exerts a feedback control on upstream growth factor signaling that includes phosphorylation and activation of GRB10 a INSR-dependent signaling suppressor (PubMed:21659604). Among other potential targets mTORC1 may phosphorylate CLIP1 and regulate microtubules (PubMed:12231510). As part of the mTORC2 complex MTOR may regulate other cellular processes including survival and organization of the cytoskeleton (PubMed:15268862, PubMed:15467718). Plays a critical role in the phosphorylation at 'Ser-473' of AKT1, a pro-survival effector of phosphoinositide 3-kinase, facilitating its activation by PDK1 (PubMed:15718470). mTORC2 may regulate the actin cytoskeleton, through phosphorylation of PRKCA, PXN and activation of the Rho-type guanine nucleotide exchange factors RHOA and RAC1A or RAC1B (PubMed:15268862). mTORC2 also regulates the phosphorylation of SGK1 at 'Ser-422' (PubMed:18925875). Regulates osteoclastogenesis by adjusting the expression of CEBPB isoforms (By similarity). Plays an important regulatory role in the circadian clock function; regulates period length and rhythm amplitude of the suprachiasmatic nucleus (SCN) and liver clocks (By similarity). Phosphorylates SQSTM1, promoting interaction between SQSTM1 and KEAP1 and subsequent inactivation of the BCR(KEAP1) complex (By similarity). {ECO:0000250|UniProtKB:P42346, ECO:0000250|UniProtKB:Q9JLN9, ECO:0000269|PubMed:12087098, ECO:0000269|PubMed:12150925, ECO:0000269|PubMed:12150926, ECO:0000269|PubMed:12231510, ECO:0000269|PubMed:12718876, ECO:0000269|PubMed:14651849, ECO:0000269|PubMed:15268862, ECO:0000269|PubMed:15467718, ECO:0000269|PubMed:15545625, ECO:0000269|PubMed:15718470, ECO:0000269|PubMed:18497260, ECO:0000269|PubMed:18762023, ECO:0000269|PubMed:18925875, ECO:0000269|PubMed:20516213, ECO:0000269|PubMed:20537536, ECO:0000269|PubMed:21576368, ECO:0000269|PubMed:21659604, ECO:0000269|PubMed:22343943, ECO:0000269|PubMed:22576015, ECO:0000269|PubMed:22692423, ECO:0000269|PubMed:23429703, ECO:0000269|PubMed:23429704, ECO:0000269|PubMed:23524951, ECO:0000269|PubMed:25438055, ECO:0000269|PubMed:25799227, ECO:0000269|PubMed:26018084, ECO:0000269|PubMed:30704899}. View more >>

GO - Biological processes (BP): 'de novo' pyrimidine nucleobase biosynthetic process [GO:0006207]; activation of protein kinase B activity [GO:0032148]; anoikis [GO:0043276]; behavioral response to pain [GO:0048266]; cardiac muscle cell development [GO:0055013]; cardiac muscle contraction [GO:0060048]; cellular response to amino acid starvation [GO:0034198]; cellular response to amino acid stimulus [GO:0071230]; cellular response to DNA damage stimulus [GO:0006974]; cellular response to hypoxia [GO:0071456]; cellular response to leucine [GO:0071233]; cellular response to leucine starvation [GO:1990253]; cellular response to nutrient levels [GO:0031669]; cellular response to osmotic stress [GO:0071470]; cellular response to starvation [GO:0009267]; cytoskeleton organization [GO:0007010]; energy reserve metabolic process [GO:0006112]; germ cell development [GO:0007281]; heart morphogenesis [GO:0003007]; heart valve morphogenesis [GO:0003179]; inflammatory response [GO:0006954]; lysosome organization [GO:0007040]; multicellular organism growth [GO:0035264]; negative regulation of apoptotic process [GO:0043066]; negative regulation of autophagy [GO:0010507]; negative regulation of calcineurin-NFAT signaling cascade [GO:0070885]; negative regulation of cell size [GO:0045792]; negative regulation of macroautophagy [GO:0016242]; neuronal action potential [GO:0019228]; nucleus localization [GO:0051647]; peptidyl-serine phosphorylation [GO:0018105]; peptidyl-threonine phosphorylation [GO:0018107]; phosphorylation [GO:0016310]; positive regulation of actin filament polymerization [GO:0030838]; positive regulation of cell growth [GO:0030307]; positive regulation of cytoplasmic translational initiation [GO:1904690]; positive regulation of epithelial to mesenchymal transition [GO:0010718]; positive regulation of gene expression [GO:0010628]; positive regulation of glycolytic process [GO:0045821]; positive regulation of keratinocyte migration [GO:0051549]; positive regulation of lamellipodium assembly [GO:0010592]; positive regulation of lipid biosynthetic process [GO:0046889]; positive regulation of myotube differentiation [GO:0010831]; positive regulation of oligodendrocyte differentiation [GO:0048714]; positive regulation of pentose-phosphate shunt [GO:1905857]; positive regulation of peptidyl-tyrosine phosphorylation [GO:0050731]; positive regulation of phosphoprotein phosphatase activity [GO:0032516]; positive regulation of stress fiber assembly [GO:0051496]; positive regulation of transcription by RNA polymerase III [GO:0045945]; positive regulation of transcription of nucleolar large rRNA by RNA polymerase I [GO:1901838]; positive regulation of translation [GO:0045727]; positive regulation of wound healing, spreading of epidermal cells [GO:1903691]; post-embryonic development [GO:0009791]; protein autophosphorylation [GO:0046777]; protein catabolic process [GO:0030163]; protein phosphorylation [GO:0006468]; regulation of actin cytoskeleton organization [GO:0032956]; regulation of cell growth [GO:0001558]; regulation of cell size [GO:0008361]; regulation of cellular response to heat [GO:1900034]; regulation of circadian rhythm [GO:0042752]; regulation of GTPase activity [GO:0043087]; regulation of locomotor rhythm [GO:1904059]; regulation of macroautophagy [GO:0016241]; regulation of membrane permeability [GO:0090559]; regulation of myelination [GO:0031641]; regulation of osteoclast differentiation [GO:0045670]; regulation of protein kinase B signaling [GO:0051896]; regulation of signal transduction by p53 class mediator [GO:1901796]; response to amino acid [GO:0043200]; response to heat [GO:0009408]; response to insulin [GO:0032868]; response to nutrient [GO:0007584]; response to nutrient levels [GO:0031667]; rhythmic process [GO:0048511]; ruffle organization [GO:0031529]; T-helper 1 cell lineage commitment [GO:0002296]; TORC1 signaling [GO:0038202]; TOR signaling [GO:0031929]; voluntary musculoskeletal movement [GO:0050882] 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.M304I	TCGA-44-6145	LUAD	TCGA	ITPFTS	DEG_SCF_FBW7_1	313:318	Mutation rewiring degron network	0.0833
p.M304I	DO25123	LUAD	ICGC	ITPFTS	DEG_SCF_FBW7_1	313:318	Mutation rewiring degron network	0.0833
p.A8S	TCGA-64-5779	LUAD	TCGA	AATTS	DEG_SPOP_SBC_1	12:16	Mutation rewiring degron network	0.2222
p.A8S	DO24930	LUAD	ICGC	AATTS	DEG_SPOP_SBC_1	12:16	Mutation rewiring degron network	0.2222
p.V21I	TCGA-A6-6781	COAD	TCGA	AATTS	DEG_SPOP_SBC_1	12:16	Mutation rewiring degron network	0.1944
p.V21I	DO8447	COAD	ICGC	AATTS	DEG_SPOP_SBC_1	12:16	Mutation rewiring degron network	0.1944
p.A9T	TCGA-A8-A08S	BRCA	TCGA	AATTS	DEG_SPOP_SBC_1	12:16	Mutation rewiring degron network	0.25
p.A9T	DO3140	BRCA	ICGC	AATTS	DEG_SPOP_SBC_1	12:16	Mutation rewiring degron network	0.25
p.G5R	TCGA-AK-3429	KIRC	TCGA	AATTS	DEG_SPOP_SBC_1	12:16	Mutation rewiring degron network	0.1389
p.G5R	DO17273	KIRC	ICGC	AATTS	DEG_SPOP_SBC_1	12:16	Mutation rewiring degron network	0.1389
p.R311C	TCGA-BR-8382	STAD	TCGA	ITPFTS	DEG_SCF_FBW7_1	313:318	Mutation rewiring degron network	0.2778
p.R311C	DO47925	STAD	ICGC	ITPFTS	DEG_SCF_FBW7_1	313:318	Mutation rewiring degron network	0.2778
p.R311H	TCGA-WS-AB45	COAD	TCGA	ITPFTS	DEG_SCF_FBW7_1	313:318	Mutation rewiring degron network	0.2778
p.R311H	DO51734	COAD	ICGC	ITPFTS	DEG_SCF_FBW7_1	313:318	Mutation rewiring degron network	0.2778
p.N18S	DO234230	ESAD	ICGC	AATTS	DEG_SPOP_SBC_1	12:16	Mutation rewiring degron network	0.2778
p.G3E	DO223142	ESCA	ICGC	AATTS	DEG_SPOP_SBC_1	12:16	Mutation substituting flanking lysine	0.1944
p.S20R	DO229019	LICA	ICGC	AATTS	DEG_SPOP_SBC_1	12:16	Mutation rewiring degron network	0.2222
p.A321V	DO228138	PBCA	ICGC	ITPFTS	DEG_SCF_FBW7_1	313:318	Mutation rewiring degron network	0.25
p.V6G	NCI-H522	lung	COSMIC	AATTS	DEG_SPOP_SBC_1	12:16	Mutation rewiring degron network	0.1667
p.R16H	QGP-1	pancreas	COSMIC	AATTS	DEG_SPOP_SBC_1	12:16	Mutation altering degron motif	0.8244
p.E4K	Hs683	central nervous system	COSMIC	AATTS	DEG_SPOP_SBC_1	12:16	Mutation rewiring degron network	0.1111

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

MTOR

UniProt ID: P42345

Entrez ID: 2475

External links: UniprotKB HGNC RefSeq COSMIC

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Kaplan plot for MTOR in