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

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, Krushna C. Patra, R. Brooks Robey and Nissim Hay ()
Additional contact information
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
R. Brooks Robey: Veterans Affairs Medical Center, White River Junction
Nissim Hay: University of Illinois at Chicago

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: 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.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-022-28440-3 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28440-3

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-28440-3

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().