TY - JOUR
T1 - A non-catalytic scaffolding activity of hexokinase 2 contributes to EMT and metastasis
AU - Blaha, Catherine S.
AU - Ramakrishnan, Gopalakrishnan
AU - Jeon, Sang Min
AU - Nogueira, Veronique
AU - Rho, Hyunsoo
AU - Kang, Soeun
AU - Bhaskar, Prashanth
AU - Terry, Alexander R.
AU - Aissa, Alexandre F.
AU - Frolov, Maxim V.
AU - Patra, Krushna C.
AU - Brooks Robey, R.
AU - Hay, Nissim
N1 - Publisher Copyright:
© 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85124776370
U2 - 10.1038/s41467-022-28440-3
DO - 10.1038/s41467-022-28440-3
M3 - Article
C2 - 35173161
AN - SCOPUS:85124776370
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 899
ER -
