Journal
NUCLEIC ACIDS RESEARCH
Volume 42, Issue 20, Pages 12483-12497Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gku953
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Funding
- Cancer Treatment and Research Trust award
- Canadian Institutes of Health Research [CIHR] [MOP 89737]
- European Union FP7, LungTarget consortium
- Cancer Treatment and Research Trust (CTRT)
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The increased cap-independent translation of antiapoptotic proteins is involved in the development of drug resistance in lung cancer but signalling events regulating this are poorly understood. Fibroblast growth factor 2 (FGF-2) signalling-induced S6 kinase 2 (S6K2) activation is necessary, but the downstream mediator(s) coupling this kinase to the translational response is unknown. Here, we showthat S6K2 binds and phosphorylates hnRNPA1 on novel Ser4/6 sites, increasing its association with BCL-XL and XIAP mRNAs to promote their nuclear export. In the cytoplasm, phosphoS4/6-hnRNPA1 dissociates from these mRNAs de-repressing their IRES-mediated translation. This correlates with the phosphorylation-dependent association of hnRNPA1 with 14-3-3 leading to hnRNPA1 sumoylation on K183 and its reimport into the nucleus. A non-phosphorylatible, S4/6A mutant prevented these processes, hindering the pro-survival activity of FGF-2/S6K2 signalling. Interestingly, immunohistochemical staining of lung and breast cancer tissue samples demonstrated that increased S6K2 expression correlates with decreased cytoplasmic hnRNPA1 and increased BCL-XL expression. In short, phosphorylation on novel N-term sites of hnRNPA1 promotes translation of antiapoptotic proteins and is indispensable for the prosurvival effects of FGF-2.
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