Association between LRRK2 and 4E-BP1 protein levels in normal and malignant cells

Berta Pons, Gemma Armengol, Mark Livingstone, Laura López, Laura Coch, Nahum Sonenberg, Santiago Ramón Y Cajal

Research output: Contribution to journalArticleResearchpeer-review

15 Citations (Scopus)

Abstract

Translational control is a crucial component of cancer development and progression. Eukaryotic initiation factor (eIF) 4E mediates eIF4F association with the mRNA 5' cap structure to stimulate cap-dependent translation initiation. The eIF4E-binding protein, 4E-BP1, regulates cap-dependent translation through its phosphorylation at multiple sites. It has been described that some human carcinomas present a high level of p-4E-BP1, not always associated with high levels of p-mTOR. These previous observations suggest that other kinases could be involved in 4E-BP1 phosporylation. Investigation in new kinases that could be implicated in 4E-BP1 phosphorylation and mechanisms that affect 4E-BP1 stability is important to understand the role of eIF4E in cell transformation. In this study, we examined 48 kinases that could be involved in 4E-BP1 phosphorylation and stability. The screening study was based on analysis of 4E-BP1 status after inhibition of these kinases in a breast carcinoma cell line. Several kinases affecting 4E-BP1 stability (LRRK2, RAF-1, p38γ, GSK3β, AMPKα, PRKACA and PRKACB) and 4E-BP1 phosphorylation (CDK1, PDK1, SRC, PRKCB1, PAK2, p38β, PRKCA and CaMKKB) were identified. These findings provide evidence that 4E-BP1 can be regulated and stabilized by multiple kinases implicated in several cell signaling pathways. We focus on the finding that LRRK2 down-regulation was associated with a clearly decreased 4E-BP1 protein (and not with mRNA down-regulation). Importantly, knockdown of LRRK2 associated with high proliferative rate in normal cells and treatment with rapamycin and/or proteosome inhibition suppressed 4E-BP1 protein degradation. These results offer new insights into the regulation of total and phosphorylated 4E-BP1.
Original languageEnglish
Pages (from-to)225-231
JournalOncology Reports
Volume27
DOIs
Publication statusPublished - 1 Jan 2012

Keywords

  • 4E-BP1
  • Kinases
  • LRRK2
  • MG132
  • Proteasome
  • Protein degradation

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