The SUMO‐E3 ligase PIAS3 targets pyruvate kinase M2

Spoden, Gilles A.; Morandell, Dieter; Ehehalt, Daniela; Fiedler, Marc; Jansen‐Dürr, Pidder; Hermann, Michael; Zwerschke, Werner

doi:10.1002/jcb.22125

Cited by 68 publications

(56 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The relative importance of these processes remains to be determined but has been shown to be essential in the glycolytic pathways of some human protozoan parasites, trypanosomes (34). Furthermore, a recent study demonstrated the interaction of SUMO-1, the SUMO E3 ligase PIAS3, and the ratelimiting glycolytic enzyme, pyruvate kinase (36). Whether this interaction of pyruvate kinase with SUMO has any effects on its enzyme activity or its interaction with other glycolytic enzymes is yet to be investigated.…”

Section: Discussionmentioning

confidence: 99%

Small Ubiquitin-related Modifier (SUMO)-1 Promotes Glycolysis in Hypoxia

Agbor

Cheong

Comerford

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Under conditions of hypoxia, most eukaryotic cells undergo a shift in metabolic strategy, which involves increased flux through the glycolytic pathway. Although this is critical for bioenergetic homeostasis, the underlying mechanisms have remained incompletely understood. Here, we report that the induction of hypoxia-induced glycolysis is retained in cells when gene transcription or protein synthesis are inhibited suggesting the involvement of additional post-translational mechanisms. Post-translational protein modification by the small ubiquitin related modifier-1 (SUMO-1) is induced in hypoxia and mass spectrometric analysis using yeast cells expressing tap-tagged Smt3 (the yeast homolog of mammalian SUMO) revealed hypoxia-dependent modification of a number of key glycolytic enzymes. Overexpression of SUMO-1 in mammalian cancer cells resulted in increased hypoxia-induced glycolysis and resistance to hypoxia-dependent ATP depletion. Supporting this, non-transformed cells also demonstrated increased glucose uptake upon SUMO-1 overexpression. Conversely, cells overexpressing the de-SUMOylating enzyme SENP-2 failed to demonstrate hypoxia-induced glycolysis. SUMO-1 overexpressing cells demonstrated focal clustering of glycolytic enzymes in response to hypoxia leading us to hypothesize a role for SUMOylation in promoting spatial re-organization of the glycolytic pathway. In summary, we hypothesize that SUMO modification of key metabolic enzymes plays an important role in shifting cellular metabolic strategies toward increased flux through the glycolytic pathway during periods of hypoxic stress.In the steady state (when oxygen levels within a cell exceed bioenergetic requirements), activity of the glycolytic pathway, the TCA (tricarboxyic acid) cycle and electron transport chain combine to generate ϳ38 molecules of adenosine triphosphate (ATP) per molecule of glucose metabolized. Glycolysis and the TCA cycle each generate 2 molecules of ATP with the remaining 34 molecules being produced during oxidative phosphorylation. This process provides the ATP necessary to maintain physiologic function. However, under conditions where oxygen demand exceeds supply (hypoxia), most cells retain the capacity to fundamentally shift metabolic strategy to a state where mitochondrial activity is decreased and glycolysis becomes the primary pathway for ATP generation (1). Normally, this metabolic switch promotes cell survival during hypoxia and is thus adaptive in nature. In such cases, cells switch back to the predominantly oxidative metabolism when the oxygen balance is restored. This phenomenon is known as the Pasteur effect (3). Alternatively, in the hypoxic compartment of a growing tumor, which has outgrown the local blood supply, the ability of cells to develop enhanced glycolytic metabolism confers a survival advantage for the tumor. Furthermore, some cancer cells develop the ability to maintain enhanced glycolysis even when sufficient oxygen supply returns, a phenomenon known as the Warburg effect (35). Thus, the ability of cell...

show abstract

Section: Discussionmentioning

confidence: 99%

Small Ubiquitin-related Modifier (SUMO)-1 Promotes Glycolysis in Hypoxia

Agbor

Cheong

Comerford

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…This isomerization of PKM2 exposes its nuclear localization sequence (NLS) and promotes its binding to importin a5, which facilitates its nuclear translocation (Yang et al, 2012c). In addition, sumoylation of PKM2 mediated by the SUMO-E3 ligase PIAS3, and acetylation of PKM2 at K433 mediated by the p300 acetyltransferase (also known as EP300) prevent the binding of FBP to PKM2, thereby enhancing its nuclear translocation (Lv et al, 2013;Spoden et al, 2009). …”

Section: Regulation Of the Subcellular Localization Of Pkm2mentioning

confidence: 99%

Pyruvate kinase M2 at a glance

Yang

2015

Journal of Cell Science

157

179

View full text Add to dashboard Cite

Reprogrammed metabolism is a key feature of cancer cells. The pyruvate kinase M2 (PKM2) isoform, which is commonly upregulated in many human cancers, has been recently shown to play a crucial role in metabolism reprogramming, gene transcription and cell cycle progression. In this Cell Science at a glance article and accompanying poster, we provide a brief overview of recent advances in understanding the mechanisms underlying the regulation of PKM2 expression, enzymatic activity, metabolic functions and subcellular location. We highlight the instrumental role of the non-metabolic functions of PKM2 in tumorigenesis and evaluate the potential to target PKM2 for cancer treatment.

show abstract

“…A variety of molecules interact with PKM2 (5,6,8,14,18,19,21,23,24,28,(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65). Many of them affect the glycolytic functions of PKM2, which directly regulate the Warburg effect.…”

Section: Nonglycolytic Functions Of Pkm2mentioning

confidence: 99%

Pyruvate Kinase M2: Multiple Faces for Conferring Benefits on Cancer Cells

Tamada

Suematsu

Saya

2012

Clinical Cancer Research

207

199

View full text Add to dashboard Cite

The M2 splice isoform of pyruvate kinase (PKM2), an enzyme that catalyzes the later step of glycolysis, is a key regulator of aerobic glycolysis (known as the Warburg effect) in cancer cells. Expression and low enzymatic activity of PKM2 confer on cancer cells the glycolytic phenotype, which promotes rapid energy production and flow of glycolytic intermediates into collateral pathways to synthesize nucleic acids, amino acids, and lipids without the accumulation of reactive oxygen species. PKM2 enzymatic activity has also been shown to be negatively regulated by the interaction with CD44 adhesion molecule, which is a cell surface marker for cancer stem cells. In addition to the glycolytic functions, nonglycolytic functions of PKM2 in cancer cells are of particular interest. PKM2 is induced translocation into the nucleus, where it activates transcription of various genes by interacting with and phosphorylating specific nuclear proteins, endowing cancer cells with a survival and growth advantage. Therefore, inhibitors and activators of PKM2 are well underway to evaluate their anticancer effects and suitability for use as novel therapeutic strategies.

show abstract

The SUMO‐E3 ligase PIAS3 targets pyruvate kinase M2

Cited by 68 publications

References 45 publications

Small Ubiquitin-related Modifier (SUMO)-1 Promotes Glycolysis in Hypoxia

Small Ubiquitin-related Modifier (SUMO)-1 Promotes Glycolysis in Hypoxia

Pyruvate kinase M2 at a glance

Pyruvate Kinase M2: Multiple Faces for Conferring Benefits on Cancer Cells

Contact Info

Product

Resources

About