TY - JOUR
T1 - eEF1A2 promotes PTEN-GSK3β-SCF complex-dependent degradation of Aurora kinase A and is inactivated in breast cancer
AU - Treekitkarnmongkol, Warapen
AU - Solis, Luisa M.
AU - Sankaran, Deivendran
AU - Gagea, Mihai
AU - Singh, Pankaj K.
AU - Mistry, Ragini
AU - Nguyen, Tristian
AU - Kai, Kazuharu
AU - Liu, Jiajun
AU - Sasai, Kaori
AU - Jitsumori, Yoshimi
AU - Liu, Jianwen
AU - Nagao, Norio
AU - Stossi, Fabio
AU - Mancini, Michael A.
AU - Wistuba, Ignacio I.
AU - Thompson, Alastair M.
AU - Lee, Jonathan M.
AU - Cadiñanos, Juan
AU - Wong, Kwong Kwok
AU - Abbott, Catherine M.
AU - Sahin, Aysegul A.
AU - Liu, Suyu
AU - Katayama, Hiroshi
AU - Sen, Subrata
N1 - Publisher Copyright:
© 2024 The Authors.
PY - 2024
Y1 - 2024
N2 - The translation elongation factor eEF1A promotes protein synthesis. Its methylation by METTL13 increases its activity, supporting tumor growth. However, in some cancers, a high abundance of eEF1A isoforms is associated with a good prognosis. Here, we found that eEF1A2 exhibited oncogenic or tumor-suppressor functions depending on its interaction with METTL13 or the phosphatase PTEN, respectively. METTL13 and PTEN competed for interaction with eEF1A2 in the same structural domain. PTEN-bound eEF1A2 promoted the ubiquitination and degradation of the mitosis-promoting Aurora kinase A in the S and G2 phases of the cell cycle. eEF1A2 bridged the interactions between the SKP1-CUL1- FBXW7 (SCF) ubiquitin ligase complex, the kinase GSK3β, and Aurora-A, thereby facilitating the phosphorylation of Aurora-A in a degron site that was recognized by FBXW7. Genetic ablation of Eef1a2 or Pten in mice resulted in a greater abundance of Aurora-A and increased cell cycling in mammary tumors, which was corroborated in breast cancer tissues from patients. Reactivating this pathway using fimepinostat, which relieves inhibitory signaling directed at PTEN and increases FBXW7 expression, combined with inhibiting Aurora-A with alisertib, suppressed breast cancer cell proliferation in culture and tumor growth in vivo. The findings demonstrate a therapeutically exploitable, tumor-suppressive role for eEF1A2 in breast cancer.
AB - The translation elongation factor eEF1A promotes protein synthesis. Its methylation by METTL13 increases its activity, supporting tumor growth. However, in some cancers, a high abundance of eEF1A isoforms is associated with a good prognosis. Here, we found that eEF1A2 exhibited oncogenic or tumor-suppressor functions depending on its interaction with METTL13 or the phosphatase PTEN, respectively. METTL13 and PTEN competed for interaction with eEF1A2 in the same structural domain. PTEN-bound eEF1A2 promoted the ubiquitination and degradation of the mitosis-promoting Aurora kinase A in the S and G2 phases of the cell cycle. eEF1A2 bridged the interactions between the SKP1-CUL1- FBXW7 (SCF) ubiquitin ligase complex, the kinase GSK3β, and Aurora-A, thereby facilitating the phosphorylation of Aurora-A in a degron site that was recognized by FBXW7. Genetic ablation of Eef1a2 or Pten in mice resulted in a greater abundance of Aurora-A and increased cell cycling in mammary tumors, which was corroborated in breast cancer tissues from patients. Reactivating this pathway using fimepinostat, which relieves inhibitory signaling directed at PTEN and increases FBXW7 expression, combined with inhibiting Aurora-A with alisertib, suppressed breast cancer cell proliferation in culture and tumor growth in vivo. The findings demonstrate a therapeutically exploitable, tumor-suppressive role for eEF1A2 in breast cancer.
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U2 - 10.1126/scisignal.adh4475
DO - 10.1126/scisignal.adh4475
M3 - Article
C2 - 38442201
AN - SCOPUS:85186874455
SN - 1945-0877
VL - 17
JO - Science signaling
JF - Science signaling
IS - 826
M1 - eadh4475
ER -