TP53 Regulates Metabolic Genes (Homo sapiens)

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5, 8, 9, 14, 16...3, 7, 11, 22, 55...643817, 61, 7436, 8312, 2313, 4936, 542, 6847, 7848, 8140, 48, 8265, 6626, 31, 605, 8, 28285219, 21, 27, 63, 69...35, 44, 4534, 687036, 4320, 51, 67, 7556, 7064, 7936, 4320, 37, 506, 2426, 31, 60771414nucleoplasmcytosolmitochondrial matrixmitochondrial intermembrane spacelysosomal lumenSESN1,2,3p-S939,T1462-TSC2:14-3-3 dimerTSC1:TSC2TP53 PRKAB1 TP53 Tetramer:PTENGeneSCO2 GeneGLS2 dimerSESN1,2,3 Genesp-S939,T1462-TSC2 TP53 COX5B H2OYWHAZ LAMTOR1 MT-CO3 RHEB glucose 6-phosphateisomerase dimerSCO2 Gene GLS2 GeneLAMTOR1 NADP+ADPH+PiGDP COX11,14,16,18,20RRM2B GeneNADPHp-S939,T1462-TSC2DDIT4 GeneYWHAG PRDX1 AMP H2OCOX7B RRAGD DDIT4DDIT4 p-S1387-TSC2 Cytochrome c(reduced)MLST8 NADP+Active AKTTP53 GSR-2 SCO2LAMTOR3 TP53 TetramerPiPTENG6PD dimer andtetramerDDIT4:14-3-3 dimerTP53 Tetramer:SCO2GeneMLST8 H+PRKAG1 RRAGB YWHAE TP53 Tetramer:TIGARGeneGDP HOOS-C52-PRDX1 dimerLAMTOR5 CYCS RPTOR SFN YWHAE GLS dimersRRAGC RHEB MTOR GLS2 Gene p-T172-PRKAA2 COX4I1 mTORC1:Ragulator:Rag:GNP:RHEB:GDPHOOS-C52-PRDX1 NH4+PRKAG3 GSHp-T172-PRKAA2 TP53 TSC2COX5A MT-CO2 NADPHSESN1,2,3:HOOS-C52-PRDX1 dimerYWHAB PRKAG2 TSC1 Metabolism ofcarbohydratesLAMTOR4 LAMTOR3 TSC1 PRDX1,2,5RRAGC COX7C ATPCOX ancilliaryproteinsTSC1:p-S1387-TSC2Metabolism ofnucleotidesADPPRKAG3 TP53 Tetramer:GLS2GeneTIGARPRKAB2 2xGSR-2:2xFADCOX8A p-T174-PRKAA1 HOOS-C52-PRDX1 H2OTP53 FAD GSSGPRKAG2 p-T174-PRKAA1 H+TP63/T53:DDIT4 GeneRPTOR Active mTORC1complexTP53 Tetramer:RRM2BGeneAMP YWHAB TIGAR GeneD-Glucono-1,5-lactone 6-phosphateRespiratory electrontransport, ATPsynthesis bychemiosmoticcoupling, and heatproduction byuncouplingproteins.TXNYWHAZ PIP3 activates AKTsignalingLAMTOR5 Detoxification ofReactive OxygenSpeciesH2O2xHC-TXNCYCS TXNRD1 H+YWHAQ GPX2 H2OTSC2 GPI ATPferroheme TP53 Cytochrome c oxidasePRKAG1 Metabolism of aminoacids andderivativesRRM2BCOX7A2L GTP PRDX1 dimerRRAGA COX6A1 MT-CO1 Energy dependentregulation of mTORby LKB1-AMPKCOX6C(3-75) GluCytochrome c(oxidised)TP53 PRDX1 SESN1,2,3:p-AMPKheterotrimer:AMPFru(6)PMTOR TSC1LAMTOR2 O2L-GlnYWHAH DDIT4 Gene p-AMPKheterotrimer:AMPRRAGB CuA LAMTOR2 H2ORRM2B Gene TP63 Tetramer/ TP53TetramerH2O2YWHAH PTEN Gene COX19D-Fructose2,6-bisphosphateSFN RRAGD GPX2 tetramerYWHAG LAMTOR4 2xTXNRD1:2xFADG6PGLS2 TP53Tetramer:SESN1,2,3GenesRRAGA PRKAB1 YWHAQ PTEN GeneTIGAR Gene COX6B1 FAD PRDX1 ferriheme PRKAB2 GTP 14-3-3 dimer4, 15, 25, 33, 41...8310, 39, 8026, 31, 602, 681, 18, 4270282036, 4336, 54486414


Description

The tumor suppressor protein TP53 (p53) regulates transcription of a number of genes involved in the metabolism of carbohydrates, nucleotides and amino acids, protein synthesis and aerobic respiration.

TP53 stimulates transcription of TIGAR, a D-fructose 2,6-bisphosphatase. TIGAR activity decreases glycolytic rate and lowers ROS (reactive oxygen species) levels in cells (Bensaad et al. 2006). TP53 may also negatively regulate the rate of glycolysis by inhibiting the expression of glucose transporters GLUT1, GLUT3 and GLUT4 (Kondoh et al. 2005, Schwartzenberg-Bar-Yoseph et al. 2004, Kawauchi et al. 2008).<p>TP53 negatively regulates several key points in PI3K/AKT signaling and downstream mTOR signaling, decreasing the rate of protein synthesis and, hence, cellular growth. TP53 directly stimulates transcription of the tumor suppressor PTEN, which acts to inhibit PI3K-mediated activation of AKT (Stambolic et al. 2001). TP53 stimulates transcription of sestrin genes, SESN1, SESN2, and SESN3 (Velasco-Miguel et al. 1999, Budanov et al. 2002, Brynczka et al. 2007). One of sestrin functions may be to reduce and reactivate overoxidized peroxiredoxin PRDX1, thereby reducing ROS levels (Budanov et al. 2004, Papadia et al. 2008, Essler et al. 2009). Another function of sestrins is to bind the activated AMPK complex and protect it from AKT-mediated inactivation. By enhancing AMPK activity, sestrins negatively regulate mTOR signaling (Budanov and Karin 2008, Cam et al. 2014). The expression of DDIT4 (REDD1), another negative regulator of mTOR signaling, is directly stimulated by TP63 and TP53. DDIT4 prevents AKT-mediated inactivation of TSC1:TSC2 complex, thus inhibiting mTOR cascade (Cam et al. 2014, Ellisen et al. 2002, DeYoung et al. 2008). TP53 may also be involved, directly or indirectly, in regulation of expression of other participants of PI3K/AKT/mTOR signaling, such as PIK3CA (Singh et al. 2002), TSC2 and AMPKB (Feng et al. 2007). <p>TP53 regulates mitochondrial metabolism through several routes. TP53 stimulates transcription of SCO2 gene, which encodes a mitochondrial cytochrome c oxidase assembly protein (Matoba et al. 2006). TP53 stimulates transcription of RRM2B gene, which encodes a subunit of the ribonucleotide reductase complex, responsible for the conversion of ribonucleotides to deoxyribonucleotides and essential for the maintenance of mitochondrial DNA content in the cell (Tanaka et al. 2000, Bourdon et al. 2007, Kulawiec et al. 2009). TP53 also transactivates mitochondrial transcription factor A (TFAM), a nuclear-encoded gene important for mitochondrial DNA (mtDNA) transcription and maintenance (Park et al. 2009). Finally, TP53 stimulates transcription of the mitochondrial glutaminase GLS2, leading to increased mitochondrial respiration rate and reduced ROS levels (Hu et al. 2010). <p>The great majority of tumor cells generate energy through aerobic glycolysis, rather than the much more efficient aerobic mitochondrial respiration, and this metabolic change is known as the Warburg effect (Warburg 1956). Since the majority of tumor cells have impaired TP53 function, and TP53 regulates a number of genes involved in glycolysis and mitochondrial respiration, it is likely that TP53 inactivation plays an important role in the metabolic derangement of cancer cells such as the Warburg effect and the concomitant increased tumorigenicity (reviewed by Feng and Levine 2010). On the other hand, some mutations of TP53 in Li-Fraumeni syndrome may result in the retention of its wild-type metabolic activities while losing cell cycle and apoptosis functions (Wang et al. 2013). Consistent with such human data, some mutations of p53, unlike p53 null state, retain the ability to regulate energy metabolism while being inactive in regulating its classic gene targets involved in cell cycle, apoptosis and senescence. Retention of metabolic and antioxidant functions of p53 protects p53 mutant mice from early onset tumorigenesis (Li et al. 2012). Source:Reactome.</div>

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History

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CompareRevisionActionTimeUserComment
114836view16:33, 25 January 2021ReactomeTeamReactome version 75
113282view11:35, 2 November 2020ReactomeTeamReactome version 74
112493view15:45, 9 October 2020ReactomeTeamReactome version 73
102617view08:09, 13 January 2019EgonwAssuming CuA is Cu2+
101405view11:29, 1 November 2018ReactomeTeamreactome version 66
100943view21:05, 31 October 2018ReactomeTeamreactome version 65
100480view19:39, 31 October 2018ReactomeTeamreactome version 64
100025view16:22, 31 October 2018ReactomeTeamreactome version 63
99578view14:55, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99200view12:43, 31 October 2018ReactomeTeamreactome version 62
93881view13:42, 16 August 2017ReactomeTeamreactome version 61
93449view11:23, 9 August 2017ReactomeTeamreactome version 61
88395view15:18, 4 August 2016FehrhartOntology Term : 'classic metabolic pathway' added !
88394view15:16, 4 August 2016FehrhartOntology Term : 'regulatory pathway' added !
86541view09:20, 11 July 2016ReactomeTeamreactome version 56
83329view10:48, 18 November 2015ReactomeTeamVersion54
81482view13:01, 21 August 2015ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
14-3-3 dimerR-HSA-1445138 (Reactome)
2xGSR-2:2xFADComplexR-HSA-71680 (Reactome)
2xHC-TXNProteinP10599 (Uniprot-TrEMBL)
2xTXNRD1:2xFADComplexR-HSA-73532 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
AMP MetaboliteCHEBI:16027 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Active AKTR-HSA-202074 (Reactome)
Active mTORC1 complexComplexR-HSA-165678 (Reactome)
COX ancilliary proteinsR-HSA-5566488 (Reactome)
COX11,14,16,18,20R-HSA-5336143 (Reactome)
COX19ProteinQ3E731 (Uniprot-TrEMBL)
COX4I1 ProteinP13073 (Uniprot-TrEMBL)
COX5A ProteinP20674 (Uniprot-TrEMBL)
COX5B ProteinP10606 (Uniprot-TrEMBL)
COX6A1 ProteinP12074 (Uniprot-TrEMBL)
COX6B1 ProteinP14854 (Uniprot-TrEMBL)
COX6C(3-75) ProteinP09669 (Uniprot-TrEMBL)
COX7A2L ProteinO14548 (Uniprot-TrEMBL)
COX7B ProteinP24311 (Uniprot-TrEMBL)
COX7C ProteinP15954 (Uniprot-TrEMBL)
COX8A ProteinP10176 (Uniprot-TrEMBL)
CYCS ProteinP99999 (Uniprot-TrEMBL)
CuA MetaboliteCHEBI:28694 (ChEBI)
Cytochrome c (oxidised)ComplexR-HSA-352607 (Reactome)
Cytochrome c (reduced)ComplexR-HSA-352609 (Reactome)
Cytochrome c oxidaseComplexR-HSA-164316 (Reactome)
D-Fructose 2,6-bisphosphateMetaboliteCHEBI:28602 (ChEBI)
D-Glucono-1,5-lactone 6-phosphateMetaboliteCHEBI:16938 (ChEBI)
DDIT4 Gene ProteinENSG00000168209 (ENSEMBL)
DDIT4 GeneENSG00000168209 (ENSEMBL)
DDIT4 ProteinQ9NX09 (Uniprot-TrEMBL)
DDIT4:14-3-3 dimerComplexR-HSA-5632741 (Reactome)
DDIT4ProteinQ9NX09 (Uniprot-TrEMBL)
Detoxification of

Reactive Oxygen

Species		PathwayR-HSA-3299685 (Reactome) Reactive oxygen species such as superoxide (O2.-), peroxides (ROOR), singlet oxygen, peroxynitrite (ONOO-), and hydroxyl radical (OH.) are generated by cellular processes such as respiration (reviewed in Murphy 2009, Brand 2010) and redox enzymes and are required for signaling yet they are damaging due to their high reactivity (reviewed in Imlay 2008, Buettner 2011, Kavdia 2011, Birben et al. 2012, Ray et al. 2012). Aerobic cells have defenses that detoxify reactive oxygen species by converting them to less reactive products. Superoxide dismutases convert superoxide to hydrogen peroxide and oxygen (reviewed in Fukai and Ushio-Fukai 2011). Catalase and peroxidases then convert hydrogen peroxide to water.
Humans contain 3 superoxide dismutases: SOD1 is located in the cytosol and mitochondrial intermembrane space, SOD2 is located in the mitochondrial matrix, and SOD3 is located in the extracellular region. Superoxide, a negative ion, is unable to easily cross membranes and tends to remain in the compartment where it was produced. Hydrogen peroxide, one of the products of superoxide dismutase, is able to diffuse across membranes and pass through aquaporin channels. In most cells the primary source of hydrogen peroxide is mitochondria and, once in the cytosol, hydrogen peroxide serves as a signaling molecule to regulate redox-sensitive proteins such as transcription factors, kinases, phosphatases, ion channels, and others (reviewed in Veal and Day 2011, Ray et al. 2012). Hydrogen peroxide is decomposed to water by catalase, decomposed to water plus oxidized thioredoxin by peroxiredoxins, and decomposed to water plus oxidized glutathione by glutathione peroxidases (Presnell et al. 2013).
Energy dependent

regulation of mTOR

by LKB1-AMPK		PathwayR-HSA-380972 (Reactome) Upon formation of a trimeric LKB1:STRAD:MO25 complex, LKB1 phosphorylates and activates AMPK. This phosphorylation is immediately removed in basal conditions by PP2C, but if the cellular AMP:ATP ratio rises, this activation is maintained, as AMP binding by AMPK inhibits the dephosphorylation. AMPK then activates the TSC complex by phosphorylating TSC2. Active TSC activates the intrinsic GTPase activity of Rheb, resulting in GDP-loaded Rheb and inhibition of mTOR pathway.
FAD MetaboliteCHEBI:16238 (ChEBI)
Fru(6)PMetaboliteCHEBI:15946 (ChEBI)
G6PMetaboliteCHEBI:17665 (ChEBI)
G6PD dimer and tetramerR-HSA-464971 (Reactome)
GDP MetaboliteCHEBI:17552 (ChEBI)
GLS dimersR-HSA-507859 (Reactome)
GLS2 Gene ProteinENSG00000135423 (ENSEMBL)
GLS2 GeneENSG00000135423 (ENSEMBL)
GLS2 ProteinQ9UI32 (Uniprot-TrEMBL)
GLS2 dimerComplexR-HSA-507858 (Reactome)
GPI ProteinP06744 (Uniprot-TrEMBL)
GPX2 ProteinP18283 (Uniprot-TrEMBL)
GPX2 tetramerComplexR-HSA-2142735 (Reactome)
GSHMetaboliteCHEBI:16856 (ChEBI)
GSR-2 ProteinP00390-2 (Uniprot-TrEMBL)
GSSGMetaboliteCHEBI:17858 (ChEBI)
GTP MetaboliteCHEBI:15996 (ChEBI)
GluMetaboliteCHEBI:16015 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2O2MetaboliteCHEBI:16240 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HOOS-C52-PRDX1 ProteinQ06830 (Uniprot-TrEMBL)
HOOS-C52-PRDX1 dimerComplexR-HSA-5631882 (Reactome)
L-GlnMetaboliteCHEBI:18050 (ChEBI)
LAMTOR1 ProteinQ6IAA8 (Uniprot-TrEMBL)
LAMTOR2 ProteinQ9Y2Q5 (Uniprot-TrEMBL)
LAMTOR3 ProteinQ9UHA4 (Uniprot-TrEMBL)
LAMTOR4 ProteinQ0VGL1 (Uniprot-TrEMBL)
LAMTOR5 ProteinO43504 (Uniprot-TrEMBL)
MLST8 ProteinQ9BVC4 (Uniprot-TrEMBL)
MT-CO1 ProteinP00395 (Uniprot-TrEMBL)
MT-CO2 ProteinP00403 (Uniprot-TrEMBL)
MT-CO3 ProteinP00414 (Uniprot-TrEMBL)
MTOR ProteinP42345 (Uniprot-TrEMBL)
Metabolism of carbohydratesPathwayR-HSA-71387 (Reactome) These pathways together are responsible for: 1) the extraction of energy and carbon skeletons for biosyntheses from dietary sugars and related molecules; 2) the short-term storage of glucose in the body (as glycogen) and its mobilization during a short fast; and 3) the synthesis of glucose from pyruvate during extended fasts.
Metabolism of nucleotidesPathwayR-HSA-15869 (Reactome) Nucleotides and their derivatives are used for short-term energy storage (ATP, GTP), for intra- and extra-cellular signaling (cAMP; adenosine), as enzyme cofactors (NAD, FAD), and for the synthesis of DNA and RNA. Most dietary nucleotides are consumed by gut flora; the human body's own supply of these molecules is synthesized de novo. Additional metabolic pathways allow the interconversion of nucleotides, the salvage and reutilization of nucleotides released by degradation of DNA and RNA, and the catabolism of excess nucleotides (Rudolph 1994). These pathways are regulated to control the total size of the intracellular nucleotide pool, to balance the relative amounts of individual nucleotides, and to couple the synthesis of deoxyribonucleotides to the onset of DNA replication (S phase of the cell cycle).

These pathways are also of major clinical interest as they are the means by which nucleotide analogues used as anti-viral and anti-tumor drugs are taken up by cells, activated, and catabolized (Weilin and Nordlund 2010). As well, differences in nuclotide metabolic pathways between humans and aplicomplexan parasites like Plasmodium have been exploited to design drugs to attack the latter (Hyde 2007).

The movement of nucleotides and purine and pyrimidine bases across lipid bilayer membranes, mediated by SLC transporters, is annotated as part of the module "transmembrane transport of small molecules".

Metabolism of amino

acids and

derivatives		PathwayR-HSA-71291 (Reactome) This group of reactions is responsible for: 1) the breakdown of amino acids; 2) the synthesis of urea from ammonia and amino groups generated by amino acid breakdown; 3) the synthesis of the ten amino acids that are not essential components of the human diet; and 4) the synthesis of related nitrogen-containing molecules including carnitine and creatine.

Transport of these molecuels across lipid bilayer membranes is annotated separately as part of the module on "transmembrane transport of small molecules".

NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
NH4+MetaboliteCHEBI:28938 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
PIP3 activates AKT signalingPathwayR-HSA-1257604 (Reactome) Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007.
PRDX1 ProteinQ06830 (Uniprot-TrEMBL)
PRDX1 dimerComplexR-HSA-3341319 (Reactome)
PRDX1,2,5R-HSA-3341359 (Reactome)
PRKAB1 ProteinQ9Y478 (Uniprot-TrEMBL)
PRKAB2 ProteinO43741 (Uniprot-TrEMBL)
PRKAG1 ProteinP54619 (Uniprot-TrEMBL)
PRKAG2 ProteinQ9UGJ0 (Uniprot-TrEMBL)
PRKAG3 ProteinQ9UGI9 (Uniprot-TrEMBL)
PTEN Gene ProteinENSG00000171862 (ENSEMBL)
PTEN GeneENSG00000171862 (ENSEMBL)
PTENProteinP60484 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
RHEB ProteinQ15382 (Uniprot-TrEMBL)
RPTOR ProteinQ8N122 (Uniprot-TrEMBL)
RRAGA ProteinQ7L523 (Uniprot-TrEMBL)
RRAGB ProteinQ5VZM2 (Uniprot-TrEMBL)
RRAGC ProteinQ9HB90 (Uniprot-TrEMBL)
RRAGD ProteinQ9NQL2 (Uniprot-TrEMBL)
RRM2B Gene ProteinENSG00000048392 (ENSEMBL)
RRM2B GeneENSG00000048392 (ENSEMBL)
RRM2BProteinQ7LG56 (Uniprot-TrEMBL)
Respiratory electron

transport, ATP synthesis by chemiosmotic coupling, and heat production by uncoupling

proteins.		PathwayR-HSA-163200 (Reactome) Oxidation of fatty acids and pyruvate in the mitochondrial matrix yield large amounts of NADH. The respiratory electron transport chain couples the re-oxidation of this NADH to NAD+ to the export of protons from the mitochonrial matrix, generating a chemiosmotic gradient across the inner mitochondrial membrane. This gradient is used to drive the synthesis of ATP; it can also be bypassed by uncoupling proteins to generate heat, a reaction in brown fat that may be important in regulation of body temperature in newborn children.
SCO2 Gene ProteinENSG00000130489 (ENSEMBL)
SCO2 GeneENSG00000130489 (ENSEMBL)
SCO2ProteinO43819 (Uniprot-TrEMBL)
SESN1,2,3 GenesR-HSA-5629150 (Reactome)
SESN1,2,3:HOOS-C52-PRDX1 dimerComplexR-HSA-5631902 (Reactome)
SESN1,2,3:p-AMPK heterotrimer:AMPComplexR-HSA-5631939 (Reactome)
SESN1,2,3R-HSA-5629191 (Reactome)
SFN ProteinP31947 (Uniprot-TrEMBL)
TIGAR Gene ProteinENSG00000078237 (ENSEMBL)
TIGAR GeneENSG00000078237 (ENSEMBL)
TIGARProteinQ9NQ88 (Uniprot-TrEMBL)
TP53

Tetramer:SESN1,2,3

Genes		ComplexR-HSA-5629180 (Reactome)
TP53 ProteinP04637 (Uniprot-TrEMBL)
TP53 Tetramer:GLS2 GeneComplexR-HSA-5632919 (Reactome)
TP53 Tetramer:PTEN GeneComplexR-HSA-5632941 (Reactome)
TP53 Tetramer:RRM2B GeneComplexR-HSA-5632886 (Reactome)
TP53 Tetramer:SCO2 GeneComplexR-HSA-5632755 (Reactome)
TP53 Tetramer:TIGAR GeneComplexR-HSA-5628900 (Reactome)
TP53 TetramerComplexR-HSA-3209194 (Reactome)
TP63 Tetramer/ TP53 TetramerR-HSA-5632387 (Reactome)
TP63/T53:DDIT4 GeneComplexR-HSA-5632392 (Reactome)
TSC1 ProteinQ92574 (Uniprot-TrEMBL)
TSC1:TSC2ComplexR-HSA-165175 (Reactome)
TSC1:p-S1387-TSC2ComplexR-HSA-381855 (Reactome)
TSC1ProteinQ92574 (Uniprot-TrEMBL)
TSC2 ProteinP49815 (Uniprot-TrEMBL)
TSC2ProteinP49815 (Uniprot-TrEMBL)
TXNProteinP10599 (Uniprot-TrEMBL)
TXNRD1 ProteinQ16881 (Uniprot-TrEMBL)
YWHAB ProteinP31946 (Uniprot-TrEMBL)
YWHAE ProteinP62258 (Uniprot-TrEMBL)
YWHAG ProteinP61981 (Uniprot-TrEMBL)
YWHAH ProteinQ04917 (Uniprot-TrEMBL)
YWHAQ ProteinP27348 (Uniprot-TrEMBL)
YWHAZ ProteinP63104 (Uniprot-TrEMBL)
ferriheme MetaboliteCHEBI:38574 (ChEBI)
ferroheme MetaboliteCHEBI:38573 (ChEBI)
glucose 6-phosphate isomerase dimerComplexR-HSA-70469 (Reactome)
mTORC1:Ragulator:Rag:GNP:RHEB:GDPComplexR-HSA-5693447 (Reactome)
p-AMPK heterotrimer:AMPComplexR-HSA-380931 (Reactome)
p-S1387-TSC2 ProteinP49815 (Uniprot-TrEMBL)
p-S939,T1462-TSC2 ProteinP49815 (Uniprot-TrEMBL)
p-S939,T1462-TSC2:14-3-3 dimerComplexR-HSA-5632727 (Reactome)
p-S939,T1462-TSC2ProteinP49815 (Uniprot-TrEMBL)
p-T172-PRKAA2 ProteinP54646 (Uniprot-TrEMBL)
p-T174-PRKAA1 ProteinQ13131 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
14-3-3 dimerR-HSA-5632732 (Reactome)
14-3-3 dimerR-HSA-5632738 (Reactome)
2xGSR-2:2xFADmim-catalysisR-HSA-71682 (Reactome)
2xHC-TXNArrowR-HSA-3341343 (Reactome)
2xHC-TXNR-HSA-73646 (Reactome)
2xTXNRD1:2xFADmim-catalysisR-HSA-73646 (Reactome)
ADPArrowR-HSA-198609 (Reactome)
ADPArrowR-HSA-380927 (Reactome)
ATPR-HSA-198609 (Reactome)
ATPR-HSA-380927 (Reactome)
Active AKTmim-catalysisR-HSA-198609 (Reactome)
Active mTORC1 complexR-HSA-380979 (Reactome)
Active mTORC1 complexmim-catalysisR-HSA-380979 (Reactome)
COX ancilliary proteinsArrowR-HSA-163214 (Reactome)
COX11,14,16,18,20ArrowR-HSA-163214 (Reactome)
COX19ArrowR-HSA-163214 (Reactome)
Cytochrome c (oxidised)ArrowR-HSA-163214 (Reactome)
Cytochrome c (reduced)R-HSA-163214 (Reactome)
Cytochrome c oxidasemim-catalysisR-HSA-163214 (Reactome)
D-Fructose 2,6-bisphosphateR-HSA-5628905 (Reactome)
D-Glucono-1,5-lactone 6-phosphateArrowR-HSA-70377 (Reactome)
DDIT4 GeneR-HSA-5632386 (Reactome)
DDIT4 GeneR-HSA-5632393 (Reactome)
DDIT4:14-3-3 dimerArrowR-HSA-5632738 (Reactome)
DDIT4:14-3-3 dimerTBarR-HSA-5632732 (Reactome)
DDIT4ArrowR-HSA-5632386 (Reactome)
DDIT4R-HSA-5632738 (Reactome)
Fru(6)PArrowR-HSA-5628905 (Reactome)
Fru(6)PR-HSA-70475 (Reactome)
G6PArrowR-HSA-70475 (Reactome)
G6PD dimer and tetramermim-catalysisR-HSA-70377 (Reactome)
G6PR-HSA-70377 (Reactome)
GLS dimersmim-catalysisR-HSA-70609 (Reactome)
GLS2 GeneR-HSA-5632914 (Reactome)
GLS2 GeneR-HSA-5632924 (Reactome)
GLS2 dimerArrowR-HSA-5632924 (Reactome)
GPX2 tetramermim-catalysisR-HSA-3341277 (Reactome)
GSHArrowR-HSA-71682 (Reactome)
GSHR-HSA-3341277 (Reactome)
GSSGArrowR-HSA-3341277 (Reactome)
GSSGR-HSA-71682 (Reactome)
GluArrowR-HSA-70609 (Reactome)
H+ArrowR-HSA-163214 (Reactome)
H+ArrowR-HSA-70377 (Reactome)
H+R-HSA-163214 (Reactome)
H+R-HSA-71682 (Reactome)
H+R-HSA-73646 (Reactome)
H2O2R-HSA-3341277 (Reactome)
H2O2R-HSA-3341343 (Reactome)
H2O2R-HSA-5631885 (Reactome)
H2OArrowR-HSA-163214 (Reactome)
H2OArrowR-HSA-3341277 (Reactome)
H2OArrowR-HSA-3341343 (Reactome)
H2OArrowR-HSA-5631885 (Reactome)
H2OR-HSA-5628905 (Reactome)
H2OR-HSA-70609 (Reactome)
HOOS-C52-PRDX1 dimerArrowR-HSA-5631885 (Reactome)
HOOS-C52-PRDX1 dimerR-HSA-5631903 (Reactome)
L-GlnR-HSA-70609 (Reactome)
NADP+ArrowR-HSA-71682 (Reactome)
NADP+ArrowR-HSA-73646 (Reactome)
NADP+R-HSA-70377 (Reactome)
NADPHArrowR-HSA-70377 (Reactome)
NADPHR-HSA-71682 (Reactome)
NADPHR-HSA-73646 (Reactome)
NH4+ArrowR-HSA-70609 (Reactome)
O2R-HSA-163214 (Reactome)
PRDX1 dimerR-HSA-5631885 (Reactome)
PRDX1 dimermim-catalysisR-HSA-5631885 (Reactome)
PRDX1,2,5mim-catalysisR-HSA-3341343 (Reactome)
PTEN GeneR-HSA-5632939 (Reactome)
PTEN GeneR-HSA-5632993 (Reactome)
PTENArrowR-HSA-5632993 (Reactome)
PiArrowR-HSA-380979 (Reactome)
PiArrowR-HSA-5628905 (Reactome)
R-HSA-163214 (Reactome) Complex IV (COX, cytochrome c oxidase) contains the hemeprotein cytochrome a and a3. It also contains copper atoms which undergo a transition from Cu+ to Cu2+ during the transfer of electrons through the complex to molecular oxygen. A bimetallic centre containing a copper atom and a heme-linked iron protein binds oxygen after 4 electrons have been picked up. Water, the final product of oxygen reduction, is then released. Oxygen is the final electron acceptor in the respiratory chain. The overall reaction can be summed as below:

4Cyt c(red.) + 12H+in + O2 -> 4Cyt c(ox.) + 2H2O + 8H+out

Four protons are taken up from the matrix side of the membrane to form the water (scalar protons). Wikstrom (1977) suggests 4 protons are additionally transferred out from the matrix to the intermembrane space.

COX ancillary proteins mediate membrane insertion, catalytic core processing, copper transport and insertion into core subunits and heme A biosynthesis (Stilburek et al. 2006, Fontanesi et al. 2006, Soto et al. 2012). To date, with the exception of an infantile encephalomyopathy caused by a defective COX6B1 and an exocrine pancreatic insufficiency caused by a defective COX4I2 gene, all Mendelian disorders presenting COX deficiency have been assigned to mutations in ancillary factors (Soto et al. 2012).
R-HSA-165179 (Reactome) A membrane-associated TSC1 (hamartin) binds TSC2 (tuberin) and recruits it to the plasma membrane where it can exert its function as a GAP (GTPase activating protein) for the small GTPase RHEB (Cai et al. 2006).
R-HSA-198609 (Reactome) AKT phosphorylates and inhibits TSC2 (tuberin), a suppressor of the TOR kinase pathway, which senses nutrient levels in the environment. TSC2 forms a TSC1:TSC2 protein complex that is a GAP (GTPase activating protein) for the RHEB G-protein. RHEB, in turn, activates the TOR kinase. Thus, an active AKT1 activates the TOR kinase, both of which are positive signals for cell growth (an increase in cell mass) and division.
The TOR kinase regulates two major processes: translation of selected mRNAs in the cell and autophagy. In the presence of high nutrient levels TOR is active and phosphorylates the 4EBP protein releasing the eukaryotic initiation factor 4E (eIF4E), which is essential for cap-dependent initiation of translation and promoting growth of the cell (PMID: 15314020). TOR also phosphorylates the S6 kinase, which is implicated in ribosome biogenesis as well as in the modification of the S6 ribosomal protein. AKT can also activate mTOR by another mechanism, involving phosphorylation of PRAS40, an inhibitor of mTOR activity.
R-HSA-3341277 (Reactome) GPX2 (located in the gastrointestinal tract, also called GPX-GI), like glutathione peroxidase 1 (GPX1, ubiquitous), reduces hydrogen peroxide (H2O2) with glutathione to yield oxidized glutathione and water (Chu et al. 1998, Faucher et al. 2003).
R-HSA-3341343 (Reactome) Peroxiredoxin 1 (PRDX1), PRDX2, and PRDX5 in the cytosol reduce hydrogen peroxide (H2O2) with thioredoxin yielding oxidized thioredoxin and water (Yamashita et al. 1999, Lee et al. 2007, Nagy et al. 2011).
R-HSA-380927 (Reactome) Activated AMPK (phosphorylated on the alpha subunit and with AMP bound) phosphorylates TSC2 (also known as tuberin) on Ser-1387, thereby activating the GTPase activating protein (GAP) activity of the Tuberous Sclerosis Complex (TSC). The TSC tumor suppressor is a critical upstream inhibitor of the mTORC1 complex. TSC is a GTPase-activating protein that stimulates the intrinsic GTPase activity of the small G-protein Rheb. This inactivates Rheb by stimulating its GTPase activity. The GDP-bound form of Rheb looses the ability to activate the kinase activity of the mTORC1 complex (Sancak et al. 2007). Loss of TSC1 or TSC2 leads to hyperactivation of mTORC1.

Phosphorylation of TSC1 and TSC2 serves as an integration point for a wide variety of environmental signals that regulate mTORC1 (Sabatini 2006). Mitogen-activated kinases including Akt, Erk, and Rsk directly phosphorylate TSC2, leading to its inactivation by an unknown mechanism. Another Akt substrate, PRAS40, was recently shown to bind and inhibit the mTORC1 complex. Upon phosphorylation by Akt, PRAS40 no longer inhibits mTORC1 (Sancak et al. 2007; Vander Haar et al. 2007).
R-HSA-380979 (Reactome) TSC2 (in the TSC complex) functions as a GTPase-activating protein and stimulates the intrinsic GTPase activity of the small G-protein Rheb. This results in the conversion of Rheb:GTP to Rheb:GDP. GDP-bound Rheb is unable to activate mTOR (Inoki et al. 2003, Tee et al. 2003). It is not demonstrated that RHEB hydrolyzes GTP when present in the mTORC1 complex; given the low affinity of RHEB for mTOR, it may dissociate from the mTORC1 complex before TSC2 stimulates hydrolysis of GTP; TSC2 may not have access to critical residues of RHEB when present inside mTORC1.
R-HSA-5628899 (Reactome) TIGAR gene possesses two TP53 (p53) binding sites, one upstream of the first exon and another within the first intron. TP53 can bind both sites, having a higher affinity for the intronic site (Bensaad et al. 2006).
R-HSA-5628901 (Reactome) TIGAR was first identified as a TP53 target through high-throughput gene expression profiling (Jen and Cheung 2005). Binding of TP53 to regulatory sequences in the TIGAR gene stimulates TIGAR transcription, although TIGAR can also be transcribed through a TP53-independent mechanism. TIGAR is induced by TP53 under low stress levels and decreases under high stress levels (Bensaad et al. 2006).
R-HSA-5628905 (Reactome) TIGAR shares similarity with PGMs (phosphoglycerate mutases), especially PFK2 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase). TIGAR possesses only the bisphosphatase domain and converts D-fructose 2,6-bisphosphate into D-fructose 6-phosphate (Bensaad et al. 2006). Reduction of fructose 2,6-bisphosphate levels correlates with decrease in glycolytic rates, which makes cells more sensitive to apoptotic stimuli (Vander Heiden et al. 2001). Alternatively, fructose 6-phosphate can be isomerized to glucose 6-phosphate, which is diverted to the pentose phosphate pathway, which can have an anti-apoptotic effect (Boada et al. 2000, Perez et al. 2000). In the pentose phosphate pathway, oxidized glutathione is reduced, and this reduced glutathione can then be used by glutathione peroxidase to remove hydrogen peroxide, thereby protecting cells from the oxidative stress (Kletzien et al. 1994, Fico et al. 2004, Tian et al. 1999). Indeed, expression of TIGAR increases reduced glutathione to oxidized glutathione ratio and lowers ROS (reactive oxygen species) levels in cells (Bensaad et al. 2006).
R-HSA-5629187 (Reactome) TP53 binds to the p53 response element in the intron 2 of SESN1 gene and stimulates transcription of SESN1 transcripts SESN1-1 and SESN1-3, also known as PA26 T2 and PA26 T3 (Velasco-Miguel et al. 1999). SESN2 gene expression is responsive to TP53, but the direct binding of TP53 to regulatory elements of SESN2 gene, although plausible based on sequence similarity with SESN1, has not been examined (Budanov et al. 2002). Rat ortholog of SESN3 was shown to possess p53 binding sites in the promoter region, but direct binding of TP53 to regulatory elements of human SESN3 has not been examined (Brynczka et al. 2007).
R-HSA-5629189 (Reactome) Sestrin genes, SESN1, SESN2 and SESN3, are upregulated in response to TP53. While direct regulation by TP53 has been demonstrated for SESN1 transcription isoforms SESN1-1 (T2) and SESN1-3 (T3), direct binding of TP53 to regulatory elements of SESN2 and SESN3 genes has not been examined, although p53-bidning site was found in the rat ortholog of SESN3 (Velasco-Miguel et al. 1999, Budanov et al. 2002, Brynczka et al. 2007).
R-HSA-5631885 (Reactome) The activity of eukaryotic PRDX1 gradually decreases with time, which is due to the overoxidation of the catalytic cysteine C52. Normally, oxidized cysteine C52-SOH is generated as a catalytic intermediate, which is subsequently reduced by thioredoxin. Occasionally, further oxidation happens, generating C52-SOOH , where the catalytic cysteine is converted to cysteine-sulfinic acid. This over-oxidation cannot be reversed by thioredoxin (Yang et al. 2002, Budanov et al. 2004). Bacterial peroxiredoxin AhpC does not undergo over-oxidation due to structural difference (Wood et al. 2003).
R-HSA-5631903 (Reactome) Sestrins (SESN1, SESN2 and likely SESN3) bind overoxidized PRDX1, in which the catalytic cysteine C52 has been converted to cysteine-sulfinic acid. Sestrins do not bind PRDX3 (Budanov et al. 2004). While several reports state that sestrins reduce overoxidized PRDX1 to the catalytically active homodimer (Budanov et al. 2004, Papadia et al. 2008, Essler et al. 2009), there are conflicting reports claiming that sestrins do not possess cysteine sulfinyl reductase activity (Woo et al. 2009).
R-HSA-5631941 (Reactome) SESN1, SESN2 and possibly SESN3 are able to bind the AMPK complex and increase its catalytic activity. The exact mechanism has not been elucidated, but recent studies suggest that sestrin-bound AMPK is resistant to inactivation through AKT-induced dephosphorylation (Budanov and Karin 2008, Cam et al. 2014).
R-HSA-5632386 (Reactome) Transcription of DDIT4 (REDD1) gene is stimulated by TP63, both during mouse embryonal development and under conditions of genotoxic and oxidative stress (Ellisen et al. 2002, Cam et al. 2014). TP53 stimulates DDIT4 transcription after TP53 activation by ionizing radiation (Ellisen et al. 2002), but it seems that TP63 is the main activator of DDIT4 transcription under stress conditions (Cam et al. 2014).
R-HSA-5632393 (Reactome) DDIT4 (REDD1) gene has a p53 response element immediately upstream of the transcription start site, and this p53 response element is able to bind both TP63 and TP53 transcription factors (Ellisen et al. 2002).
R-HSA-5632732 (Reactome) Phosphorylation of TSC2 by AKT enables association of TSC2 with 14-3-3 proteins YWHAB (14-3-3 protein beta/alpha), YWHAQ (14-3-3 protein theta), YWHAG (14-3-3 protein gamma), YWHAH (14-3-3 protein eta), YWHAE (14-3-3 protein epsilon), YWHAZ (14-3-3 protein zeta/delta) or SFN (14-3-3 protein sigma) (Liu et al. 2002). Binding to 14-3-3 proteins sequesters TSC2 to the cytosol and prevents its association with TSC1 (Cai et al. 2006).
R-HSA-5632738 (Reactome) DDIT4 (REDD1) binds 14-3-3 proteins through a conserved 14-3-3 binding motif Arg-X-X-X-Ser/Thr-X-Pro (DeYoung et al. 2008). Binding of DDIT4 to 14-3-3 proteins competes with 14-3-3 binding to TSC2 and thus prevents AKT-mediated inactivation of TSC2 (Cam et al. 2014).
R-HSA-5632759 (Reactome) TP53 binds the p53 response element in the intron 1 of SCO2 (Synthesis of Cytochrome c Oxidase 2) gene (Matoba et al. 2006). The binding of TP53 on SCO2 gene was verified in a genome wide chromatin immunoprecipitation study (Wei et al. 2006). Tp53 was also found to bind to the promoter region in mouse Sco2 gene to stimulate its expression in response to physical exercise (Qi et al. 2011).
R-HSA-5632766 (Reactome) TP53 directly stimulates the transcription of the SCO2 gene. SCO2, synthesis of cytochrome c oxidase 2, is a copper-binding assembly protein for the mitochondrial COX (cytochrome C oxidase) complex which enables aerobic respiration. When SCO2 levels are reduced, as occurs in TP53 deficient cells, the glycolysis becomes the main energy source for the cell. The TP53-mediated regulation of SCO2 and other mitochondrial biogenesis genes provides a possible explanation for the Warburg effect (Warburg 1956) observed in some cancer cells (Matoba et al. 2006).
R-HSA-5632887 (Reactome) TP53 binds the p53-binding site in the first intron of RRM2B (p53R2) gene (Tanaka et al. 2000).
R-HSA-5632892 (Reactome) TP53 directly stimulates transcription of RRM2B gene (p53R2), which encodes a subunit of the ribonucleotide reductase complex (Tanaka et al. 2000), responsible for de novo conversion of ribonucleotides (NTPs) to deoxyribonucleotides (dNTPs), essential for DNA synthesis. Mutations in RRM2B gene cause severe mitochondrial DNA depletion (Bourdon et al. 2007, Kulawiec et al. 2009).
R-HSA-5632914 (Reactome) The mitochondrial glutaminase GLS2 gene possesses two putative p53-binding sites in its promoter and one putative p53 binding site in the first intron. TP53 was demonstrated to bind to p53-response elements in the promoter but not intron 1 of GLS2 (Hu et al. 2010).
R-HSA-5632924 (Reactome) TP53 directly stimulates transcription of mitochondrial glutaminase GLS2 under non-stress and stress conditions. Increased GLS2 levels lead to increased production of glutamate and alpha-ketoglutarate, increased mitochondrial respiration rate, and reduced ROS (reactive oxygen species) load through enhanced glutathione reduction (Hu et al. 2010).
R-HSA-5632939 (Reactome) TP53 binds to the p53-binding site in PTEN promoter (Stambolic et al. 2001).
R-HSA-5632993 (Reactome) TP53 stimulates transcription of PTEN gene, which acts as a negative regulator of PI3K/AKT signaling (Stambolic et al. 2000, Singh et al. 2002).
R-HSA-70377 (Reactome) Cytosolic glucose-6-phosphate dehydrogenase (G6PD) catalyzes the reaction of glucose 6-phosphate and NADP+ to form D-glucono-1,5-lactone 6-phosphate and NADPH + H+. Biochemical studies indicate that both G6PD dimers and tetramers are catalytically active and capable or forming under physiological conditions in vivo (Au et al. 2000). Mutations that reduce the catalytic efficiency of G6PD are remarkably common in human populations; these appear to have a protective effect against malaria (e.g., Luzzatto and Afolayan 1968).
R-HSA-70475 (Reactome) The reversible isomerization of fructose-6-phosphate to form glucose-6-phosphate is catalyzed by cytosolic phosphoglucose isomerase (Noltman 1972; Xu and Beutler 1994; Tsuboi et al. 1958).
R-HSA-70609 (Reactome) Mitochondrial glutaminase (GLS) catalyzes the hydrolysis of glutamine to yield glutamate and ammonia. Two GLS enzymes have been identified, one abundantly expressed in the liver (GLS - Elgadi et al. 1999) and one abundantly expressed in kidney (GLS2 - Gomez-Fabre et al. 2000). Their biochemical properties are similar. The enzymes are inferred to function as dimers based on unpublished crystallographic data for GLS (PDB 3CZD) and studies of glutaminase enzyme purified from Ehrlich Ascites cells (Quesada et al. 1988).
R-HSA-71682 (Reactome) Cytosolic glutathione reductase catalyzes the reaction of glutathione (oxidized) and NADPH + H+ to form two molecules of glutathione (reduced) and NADP+ (Scott et al. 1963, Loos et al. 1976). Deficiency of glutathione reductase can cause hemolytic anemia.
R-HSA-73646 (Reactome) Cytosolic thioredoxin reductase catalyzes the reaction of thioredoxin, oxidized and NADPH + H+ to form thioredoxin, reduced and NADP+ (Urig et al. 2006).
RRM2B GeneR-HSA-5632887 (Reactome)
RRM2B GeneR-HSA-5632892 (Reactome)
RRM2BArrowR-HSA-5632892 (Reactome)
SCO2 GeneR-HSA-5632759 (Reactome)
SCO2 GeneR-HSA-5632766 (Reactome)
SCO2ArrowR-HSA-5632766 (Reactome)
SESN1,2,3 GenesR-HSA-5629187 (Reactome)
SESN1,2,3 GenesR-HSA-5629189 (Reactome)
SESN1,2,3:HOOS-C52-PRDX1 dimerArrowR-HSA-5631903 (Reactome)
SESN1,2,3:p-AMPK heterotrimer:AMPArrowR-HSA-5631941 (Reactome)
SESN1,2,3ArrowR-HSA-5629189 (Reactome)
SESN1,2,3R-HSA-5631903 (Reactome)
SESN1,2,3R-HSA-5631941 (Reactome)
TIGAR GeneR-HSA-5628899 (Reactome)
TIGAR GeneR-HSA-5628901 (Reactome)
TIGARArrowR-HSA-5628901 (Reactome)
TIGARmim-catalysisR-HSA-5628905 (Reactome)
TP53

Tetramer:SESN1,2,3

Genes		ArrowR-HSA-5629187 (Reactome)
TP53

Tetramer:SESN1,2,3

Genes		ArrowR-HSA-5629189 (Reactome)
TP53 Tetramer:GLS2 GeneArrowR-HSA-5632914 (Reactome)
TP53 Tetramer:GLS2 GeneArrowR-HSA-5632924 (Reactome)
TP53 Tetramer:PTEN GeneArrowR-HSA-5632939 (Reactome)
TP53 Tetramer:PTEN GeneArrowR-HSA-5632993 (Reactome)
TP53 Tetramer:RRM2B GeneArrowR-HSA-5632887 (Reactome)
TP53 Tetramer:RRM2B GeneArrowR-HSA-5632892 (Reactome)
TP53 Tetramer:SCO2 GeneArrowR-HSA-5632759 (Reactome)
TP53 Tetramer:SCO2 GeneArrowR-HSA-5632766 (Reactome)
TP53 Tetramer:TIGAR GeneArrowR-HSA-5628899 (Reactome)
TP53 Tetramer:TIGAR GeneArrowR-HSA-5628901 (Reactome)
TP53 TetramerR-HSA-5628899 (Reactome)
TP53 TetramerR-HSA-5629187 (Reactome)
TP53 TetramerR-HSA-5632759 (Reactome)
TP53 TetramerR-HSA-5632887 (Reactome)
TP53 TetramerR-HSA-5632914 (Reactome)
TP53 TetramerR-HSA-5632939 (Reactome)
TP63 Tetramer/ TP53 TetramerR-HSA-5632393 (Reactome)
TP63/T53:DDIT4 GeneArrowR-HSA-5632386 (Reactome)
TP63/T53:DDIT4 GeneArrowR-HSA-5632393 (Reactome)
TSC1:TSC2ArrowR-HSA-165179 (Reactome)
TSC1:TSC2R-HSA-380927 (Reactome)
TSC1:p-S1387-TSC2ArrowR-HSA-380927 (Reactome)
TSC1:p-S1387-TSC2ArrowR-HSA-380979 (Reactome)
TSC1R-HSA-165179 (Reactome)
TSC2R-HSA-165179 (Reactome)
TSC2R-HSA-198609 (Reactome)
TXNArrowR-HSA-73646 (Reactome)
TXNR-HSA-3341343 (Reactome)
glucose 6-phosphate isomerase dimermim-catalysisR-HSA-70475 (Reactome)
mTORC1:Ragulator:Rag:GNP:RHEB:GDPArrowR-HSA-380979 (Reactome)
p-AMPK heterotrimer:AMPR-HSA-5631941 (Reactome)
p-AMPK heterotrimer:AMPmim-catalysisR-HSA-380927 (Reactome)
p-S939,T1462-TSC2:14-3-3 dimerArrowR-HSA-5632732 (Reactome)
p-S939,T1462-TSC2ArrowR-HSA-198609 (Reactome)
p-S939,T1462-TSC2R-HSA-5632732 (Reactome)

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