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Multiverse of phosphorglycerate kinase: Exploring canonical, moonlighting, and tumor microenvironmental functions

Han-Hsi Kuo1, Zhao-Jing He1, Phi Ngoc Tram2

  • 1Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan.

Biochimica Et Biophysica Acta. Molecular Basis of Disease
|October 16, 2025
PubMed

Insights

Phosphoglycerate kinase (PGK) proteins have non-enzymatic roles in cancer, influencing tumor progression and the tumor microenvironment. Targeting these "moonlighting" functions offers new therapeutic strategies.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Phosphoglycerate kinase (PGK) family members, PGK1 and PGK2, are known glycolytic enzymes.
  • Emerging evidence reveals diverse non-enzymatic 'moonlighting' functions for PGK1 and PGK2.
  • These functions are critical in cancer biology, impacting signaling, extracellular matrix, immunity, and metastasis.

Purpose of the Study:

  • To reevaluate the moonlighting functions of PGKs in tumor progression and the tumor microenvironment (TME).
  • To highlight PGKs' roles in extracellular signaling, stress adaptation, and immune evasion.
  • To integrate novel post-translational modifications of PGKs.

Main Methods:

  • Review of existing literature on PGK functions beyond canonical glycolysis.
  • Analysis of studies focusing on PGK's roles within the tumor microenvironment.
  • Integration of data on post-translational modifications of PGKs.

Main Results:

  • PGK1 and PGK2 exhibit context-dependent, spatially organized functions within the TME.
  • These proteins act as stress sensors and regulators of immune responses.
  • Evidence supports their involvement in extracellular signaling and immune evasion.

Conclusions:

  • PGKs possess significant non-enzymatic, cancer-promoting activities.
  • Targeting these moonlighting functions presents novel therapeutic opportunities.
  • Understanding PGK's multifaceted roles is crucial for cancer treatment strategies.
Keywords:
Immune responseMoonlightingPhosphoglycerate kinasePost-translational modificationTumor microenvironment

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