mTORC2 deploys the mRNA binding protein IGF2BP1 to regulate c-MYC expression and promote cell survival

• Published in: Cellular signalling Vol. 80; p. 109912
• Main Authors: Lambrianidou, Andromachi, Sereti, Evangelia, Soupsana, Katerina, Komini, Chrysoula, Dimas, Konstantinos, Trangas, Theoni
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.04.2021
• Subjects: Adaptor Proteins, Vesicular Transport - genetics; Adaptor Proteins, Vesicular Transport - metabolism; Animals; Apoptosis; Apoptosis - drug effects; Benzodioxoles - pharmacology; C-MYC; Cell Survival - drug effects; Female; Humans; IGF2BP1; Mechanistic Target of Rapamycin Complex 2 - metabolism; Mice; Mice, Inbred NOD; mTORC2 kinase; Naphthyridines - pharmacology; Naphthyridines - therapeutic use; Neoplasms - drug therapy; Neoplasms - pathology; Phosphorylation; Proto-Oncogene Proteins c-myc - antagonists & inhibitors; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Quinazolines - pharmacology; RNA Interference; RNA Stability; RNA, Messenger - metabolism; RNA, Small Interfering - metabolism; RNA-Binding Proteins - antagonists & inhibitors; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Src kinase; Transplantation, Heterologous; mTORC2 kinase; MNK1; RNA; DHX9; DMSO; C-MYC; Src kinase; HNRNPU; SrcI1; RRM; DMEM; SYNCRIP; FBS; IGF2BP1; B-TrCP1/ BTRC; PBS; ZBP1; eIF4E; UTRs; IGF2; mRNPs; PAGE; siRNA; Akt; PTMs; CRD; IRES; YΒΧ1; CRDBP1; ERK1 / 2; RNPs; mTORC2; GAPDH; PCR; Apoptosis
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2020.109912

mTORC2 promotes cell survival by phosphorylating AKT and enhancing its activity. Inactivation of mTORC2 reduces viability through down-regulation of E2F1 caused by up-regulation of c-MYC. An additional target of mTORC2 is IGF2BP1, an oncofetal RNA binding protein expressed de novo in a wide array of malignancies. IGF2BP1 enhances c-MYC expression by protecting the coding region instability sequence (CRD) of its mRNA from endonucleolytic cleavage. Here we show that repression of mTORC2 signalling and prevention of Ser181 phosphorylation of IGF2BP1 enhanced translation and destabilization of the endogenous c-myc mRNA as well as the mRNA of reporter transcripts carrying the CRD sequence in frame. The consequent increase in c-MYC protein was accompanied by the emergence of an apoptotic c-MYC overexpressing population. On the other hand, preventing phosphorylation of IGF2BP1 on Tyr396 by Src kinase caused the accumulation of translationally silent transcripts through sequestration by IGF2BP1 into cytoplasmic granules. The apoptotic effect of mTORC2 signalling deprivation was augmented when preceded by inhibition of IGF2BP1 phosphorylation by the Src kinase in concert with further increase of c-MYC levels because of enhanced translation of the previously stored mRNA only in the presence of IGF2BP1. Furthermore, the combined administration of mTORC2 and Src inhibitors exhibited synergism in delaying xenograft growth in female NOD.CB17-Prkdcscid/J mice. The above in vitro and in vivo findings may be applied for the induction of targeted apoptosis of cells expressing de novo the oncofetal protein IGF2BP1, a feature of aggressive malignancies resulting in a more focused anticancer therapeutic approach. [Display omitted] •Prevention of phosphorylation of IGF2BP1 by mTORC2 enhances translation of c-myc mRNA.•Upon prevention of IGF2BP1 phosphorylation by Src c-myc mRNA is silenced and stored in granules.•Sequential inhibition of the two kinases results in overexpression of c-MYC.•The drug induced overexpression of c-MYC causes apoptosis in IGF2BP1 expressing cells.•The combined administration of kinase inhibitors retards the growth of xenografts.