Warburg effect modulated by deubiquitinating enzymes and their substrates (Homo sapiens)

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3VEGFOTUB2PGK1-acPGAM13PGGLUT1HIF-1αUSP28OTUD7BOTUB2AKT1OTUD6BOTUB2LactateLDHAG6PCUSP19GlucoseFBP1PyruvateOTUB2USP44PI3KMTORUSP19OTUD6B1,3-BPGHIF-1αFOXO1VHLGA3PG6PUSP7U2AF2SIRT7OTUB2F1,6BPPEPOTUB2HK2c-MycPyruvateUSP19USP7Glucose124F6P2PGFOXO1USP7USP37USP37OTUB2OTUB2OTUD7BOTUD6BUSP19HIF-1αc-MycUSP28USP37OTUB2USP37OTUB2OTUD7BOTUD6BUSP19PGK1


Description

Even in the presence of oxygen, cancer cells convert glucose to lactate as their main source for energy production, instead of using the citric acid cycle and oxidative phosphorylation. This process is called the Warburg effect. This pathway shows the effects deubiquitinating enzymes (DUBs) and their substrates have. DUBs free proteins of their ubiquitin chain, so that the proteins can resume their function in the cells rather than be degraded by the ubiquitin-proteasome system (UPS).

The deubiquitination of VHL via OTUD6B (part of a DUB subfamily) represses HIF-1α, whereas the direct deubiquitination of HIF-1a via DUBs leads to the increased expression of GLUT1 and VEGF. The transcription factor c-Myc helps regulate gene expression involved in the glucose metabolism (e.g., GLUT1, HK2, LDHA) and is stabilised by ubiquitin-specific proteases. The PI3K/Akt pathway is also upregulated by deubiquitination of VEGF and Akt. This entails cell growth and apoptosis regulation, as well as promoted glucose transport to cancer cells and activating mTor, which improves glycolysis. It is shown in this pathway, how deubiquitinating enzymes play an important role in stabilizing different proteins, acting as oncoproteins and tumor suppressors equally.

This pathway is based on figure 3 featured in “Regulation of Cancer Metabolism by Deubiquitinating Enzymes: The Warburg Effect” by So-Hee Kim and Kwang-Hyun Baek.

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Ontology Terms

 

Bibliography

  1. Behrman EJ, Gopalan V; ''Phosphoenolpyruvate: An end to hand-waving.''; Biochem Mol Biol Educ, 2008 PubMed Europe PMC Scholia
  2. Arafeh R, Samuels Y; ''PIK3CA in cancer: The past 30 years.''; Semin Cancer Biol, 2019 PubMed Europe PMC Scholia
  3. So-Hee Kim: Kwang-hyun Baek; ''Regulation of Cancer Metabolism by Deubiquitinating Enzymes: The Warburg Effect''; https://doi.org/10.3390/IJMS22126173, 2021 DOI Scholia
  4. Claesson-Welsh L, Welsh M; ''VEGFA and tumour angiogenesis.''; J Intern Med, 2013 PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
126981view12:23, 12 July 2023Marlen madded VEGFR2 and state (Ac)
126980view11:47, 12 July 2023Marlen mModified description
126978view19:06, 11 July 2023Marlen madded modification of PGK1
126977view18:34, 11 July 2023Marlen mModified description
126971view19:11, 10 July 2023Marlen mModified description
126968view09:07, 9 July 2023Marlen madded missing connections and steps in pathway
126965view20:06, 8 July 2023EgonwFixed a typo
126964view19:11, 8 July 2023EgonwCorrect data source
126963view10:12, 8 July 2023Marlen mcorrected PEG to PEP and added missing database references
126962view08:38, 8 July 2023Marlen mAdded database reference for gene products
126945view13:13, 7 July 2023Marlen mremoved unconnected interaction between 2PG and PEP
126903view17:26, 30 June 2023Marlen mReverted to version '13:54, 30. Jun. 2023' by Marlen m
126902view17:24, 30 June 2023Marlen mReverted to version '14:11, 29. Dez. 2022' by Marlen m
126900view13:54, 30 June 2023Marlen mfixed connection between USP44 and FBP1
124891view14:11, 29 December 2022EgonwModified title
124890view14:07, 29 December 2022EgonwManually added the DOI identifier as identifier too
122594view10:30, 20 April 2022EweitzModified description
122593view10:29, 20 April 2022EweitzModified title
122336view22:21, 19 March 2022Andramain reference
122335view22:17, 19 March 2022AndraOntology Term : 'cancer' added !
122334view22:17, 19 March 2022AndraOntology Term : 'glycolysis pathway' added !
122333view22:16, 19 March 2022AndraModified description
122332view22:13, 19 March 2022AndraNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
1,3-BPGMetabolite89363 (ChEBI)
2PGMetabolite24344 (ChEBI)
3PGMetabolite17050 (ChEBI)
AKT1GeneProduct207 (Entrez Gene)
F1,6BPMetabolite32966 (ChEBI)
F6PMetabolite61527 (ChEBI)
FBP1GeneProductFBP1 (HGNC)
FOXO1GeneProduct2308 (Entrez Gene)
G6PMetabolite4170 (ChEBI)
G6PCGeneProduct2538 (Entrez Gene)
GA3PMetabolite17138 (ChEBI)
GLUT1GeneProductENSG00000117394 (Ensembl)
GlucoseMetabolite4167 (ChEBI)
HIF-1αGeneProduct3091 (Entrez Gene)
HK2GeneProductENSG00000159399 (Ensembl)
LDHAGeneProduct3939 (Entrez Gene)
LactateMetabolite24996 (ChEBI)
MTORGeneProduct2475 (Entrez Gene)
OTUB2GeneProduct78990 (Entrez Gene)
OTUD6BGeneProduct51633 (Entrez Gene)
OTUD7BGeneProduct56957 (Entrez Gene)
PEPMetabolite18021 (ChEBI)
PGAM1GeneProduct5223 (Entrez Gene)
PGK1-acGeneProduct5230 (Entrez Gene)
PGK1GeneProduct5230 (Entrez Gene)
PI3KGeneProductENSG00000121879 (Ensembl)
PyruvateMetabolite15361 (ChEBI)
SIRT7GeneProduct51547 (Entrez Gene)
U2AF2GeneProduct11338 (Entrez Gene)
USP19GeneProduct10869 (Entrez Gene)
USP28GeneProduct57646 (Entrez Gene)
USP37GeneProduct57695 (Entrez Gene)
USP44GeneProduct84101 (Entrez Gene)
USP7GeneProduct7874 (Entrez Gene)
VEGFGeneProductENSG00000112715 (Ensembl)
VHLGeneProductENSG00000134086 (Ensembl)
c-MycGeneProductENSG00000136997 (Ensembl)

Annotated Interactions

No annotated interactions

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