Translational control is a crucial component of cancer development and progression. Eukaryotic initiation factor 4E (eIF4E) 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. The search for new kinases that could be implicated in 4E-BP1 phosphorylation, and determination of the mechanisms that affect 4E-BP1 stability are important to understand the role of eIF4E in cell transformation. In this study, we investigate 48 kinases that may be implicated 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 (MDA-MB 231 cells). With the use of this method, several kinases that affect 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 novel findings provide evidence that 4E-BP1 can be regulated and stabilized by multiple kinases implicated in several cell signaling pathways. We also found that LRRK2 downregulation affects 4E-BP1 stability and causes degradation of this factor in various cell types. Interestingly, inhibition of proteasome activity by MG132 restored total 4E-BP1 protein levels in cells where LRRK2 was downregulated. In addition, these stabilization events appear to be functionally important for cell growth control in normal cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1939. doi:10.1158/1538-7445.AM2011-1939
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