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A non-catalytic scaffolding activity of hexokinase 2 contributes to EMT and metastasis

Author

Listed:
  • Catherine S. Blaha

    (University of Illinois at Chicago)

  • Gopalakrishnan Ramakrishnan

    (University of Illinois at Chicago)

  • Sang-Min Jeon

    (Ajou University Yeongtong-gu)

  • Veronique Nogueira

    (University of Illinois at Chicago)

  • Hyunsoo Rho

    (University of Illinois at Chicago)

  • Soeun Kang

    (University of Illinois at Chicago)

  • Prashanth Bhaskar

    (University of Illinois at Chicago)

  • Alexander R. Terry

    (University of Illinois at Chicago)

  • Alexandre F. Aissa

    (University of Illinois at Chicago)

  • Maxim V. Frolov

    (University of Illinois at Chicago)

  • Krushna C. Patra

    (University of Illinois at Chicago
    University of Cincinnati)

  • R. Brooks Robey

    (Veterans Affairs Medical Center, White River Junction
    Geisel School of Medicine at Dartmouth)

  • Nissim Hay

    (University of Illinois at Chicago
    Jesse Brown VA Medical Center)

Abstract

Hexokinase 2 (HK2), which catalyzes the first committed step in glucose metabolism, is induced in cancer cells. HK2’s role in tumorigenesis has been attributed to its glucose kinase activity. Here, we describe a kinase independent HK2 activity, which contributes to metastasis. HK2 binds and sequesters glycogen synthase kinase 3 (GSK3) and acts as a scaffold forming a ternary complex with the regulatory subunit of protein kinase A (PRKAR1a) and GSK3β to facilitate GSK3β phosphorylation and inhibition by PKA. Thus, HK2 functions as an A-kinase anchoring protein (AKAP). Phosphorylation by GSK3β targets proteins for degradation. Consistently, HK2 increases the level and stability of GSK3 targets, MCL1, NRF2, and particularly SNAIL. In addition to GSK3 inhibition, HK2 kinase activity mediates SNAIL glycosylation, which prohibits its phosphorylation by GSK3. Finally, in mouse models of breast cancer metastasis, HK2 deficiency decreases SNAIL protein levels and inhibits SNAIL-mediated epithelial mesenchymal transition and metastasis.

Suggested Citation

  • Catherine S. Blaha & Gopalakrishnan Ramakrishnan & Sang-Min Jeon & Veronique Nogueira & Hyunsoo Rho & Soeun Kang & Prashanth Bhaskar & Alexander R. Terry & Alexandre F. Aissa & Maxim V. Frolov & Krush, 2022. "A non-catalytic scaffolding activity of hexokinase 2 contributes to EMT and metastasis," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28440-3
    DOI: 10.1038/s41467-022-28440-3
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    References listed on IDEAS

    as
    1. Dannielle DeWaal & Veronique Nogueira & Alexander R. Terry & Krushna C. Patra & Sang-Min Jeon & Grace Guzman & Jennifer Au & Christopher P. Long & Maciek R. Antoniewicz & Nissim Hay, 2018. "Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    2. Majd M. Ariss & Abul B. M. M. K. Islam & Meg Critcher & Maria Paula Zappia & Maxim V. Frolov, 2018. "Single cell RNA-sequencing identifies a metabolic aspect of apoptosis in Rbf mutant," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    3. Kyle J. Travaglini & Ahmad N. Nabhan & Lolita Penland & Rahul Sinha & Astrid Gillich & Rene V. Sit & Stephen Chang & Stephanie D. Conley & Yasuo Mori & Jun Seita & Gerald J. Berry & Joseph B. Shrager , 2020. "A molecular cell atlas of the human lung from single-cell RNA sequencing," Nature, Nature, vol. 587(7835), pages 619-625, November.
    4. Dannielle DeWaal & Veronique Nogueira & Alexander R. Terry & Krushna C. Patra & Sang-Min Jeon & Grace Guzman & Jennifer Au & Christopher P. Long & Maciek R. Antoniewicz & Nissim Hay, 2018. "Author Correction: Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin," Nature Communications, Nature, vol. 9(1), pages 1-1, December.
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