title: Association between LRRK2 and 4E-BP1 protein levels in normal and malignant             cells.
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.
authors.affiliation: Department of Pathology, Vall d'Hebron University Hospital, Faculty of Biosciences, and Department of Biochemistry and Molecular Biology, Universitat Autónoma de Barcelona, Barcelona, Spain.
authors.forename: Berta
authors.initials: B
authors.lastname: Pons
authors.forename: Gemma
authors.initials: G
authors.lastname: Armengol
authors.forename: Mark
authors.initials: M
authors.lastname: Livingstone
authors.forename: Laura
authors.initials: L
authors.lastname: López
authors.forename: Laura
authors.initials: L
authors.lastname: Coch
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
authors.forename: Santiago
authors.initials: S
authors.lastname: Ramón y Cajal
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D015153:Blotting, Western; D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D009369:Neoplasms / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D055550:Protein Stability; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D010750:Phosphoproteins; D034741:RNA, Small Interfering; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases