Posttranslational Modifications of Pyruvate Kinase M2: Tweaks that Benefit Cancer.

Gopinath Prakasam,Rameshwar N K Bamezai,Mohammad Askandar Iqbal,Sybille Mazurek

doi:10.3389/fonc.2018.00022

Abstract

Cancer cells rewire metabolism to meet biosynthetic and energetic demands. The characteristic increase in glycolysis, i.e., Warburg effect, now considered as a hallmark, supports cancer in various ways. To attain such metabolic reshuffle, cancer cells preferentially re-express the M2 isoform of pyruvate kinase (PKM2, M2-PK) and alter its quaternary structure to generate less-active PKM2 dimers. The relatively inactive dimers cause the accumulation of glycolytic intermediates that are redirected into anabolic pathways. In addition, dimeric PKM2 also benefits cancer cells through various non-glycolytic moonlight functions, such as gene transcription, protein kinase activity, and redox balance. A large body of data have shown that several distinct posttranslation modifications (PTMs) regulate PKM2 in a way that benefits cancer growth, e.g., formation of PKM2 dimers. This review discusses the recent advancements in our understanding of various PTMs and the benefits they impart to the sustenance of cancer. Understanding the PTMs in PKM2 is crucial to assess their therapeutic potential and to design novel anticancer strategies.

Highlights

The key metabolic anomaly associated with tumor cells in contrast to their non-transformed counterparts is rewiring of metabolism to escalate glucose uptake rate and to break down glucose largely into lactate, regardless of the presence of oxygen, a phenomenon known as aerobic glycolysis or Warburg effect [1]
AKT stimulated by insulinlike growth factor (IGF-1) in cancer cells has been shown to interact and phosphorylate PKM2 at the S202 residue to promote its entry into the nucleus to facilitate the transcriptional activation of signal transducer and activator of transcription (STAT)5A
This study proposes PKM2 as a coactivator of the transcription factor, STAT5A, which functions downstream to the IGF/PI3K/AKT signaling pathway to promote tumor growth [56]

Summary

INTRODUCTION

The key metabolic anomaly associated with tumor cells in contrast to their non-transformed counterparts is rewiring of metabolism to escalate glucose uptake rate and to break down glucose largely into lactate, regardless of the presence of oxygen, a phenomenon known as aerobic glycolysis or Warburg effect [1]. Mammalian target of rapamycin (mTOR), downstream to the axis of receptor tyrosine kinase/PI3K/protein kinase B (AKT), which is frequently deregulated in cancer cells, is known to stimulate the expression of c-Myc and normoxic stabilization of HIF-1 Both transcription factors increase the transcriptional activation of many glycolytic enzymes including PKM2 to stimulate aerobic glycolysis [22]. Unlike other isoforms of PK, PKM2 harbors numerous conserved PTM sites, often modified by phosphorylation, acetylation, prolylhydroxylation, oxidation, ubiquitination, and sumoylation in res ponse to various stimuli in cancer cells (Figure 1B) These PTMs modulate structural and functional properties of PKM2, such as oligomeric state, catalytic activity, binding of allosteric activators, protein stability, conditional protein interaction, and subcellular localization. The posttranslationally modified PKM2 provides metabolic and non-metabolic benefits to cancer cells

Tyrosine Phosphorylation

UBIQUITINATION AND SUMOYLATION

Arginine methylation

CONCLUDING REMARKS