title: hnRNPA1 couples nuclear export and translation of specific mRNAs downstream of FGF-2/S6K2 signalling.
abstract: The increased cap-independent translation of anti-apoptotic 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 show that 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 re-import 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 anti-apoptotic proteins and is indispensable for the pro-survival effects of FGF-2.
authors.affiliation: Division of Cancer, Department of Surgery and Cancer, 1st Floor, ICTEM Building, Hammersmith Hospitals Campus of Imperial College London, Du Cane Road, London W12 0NN, UK.
authors.forename: Rajat
authors.initials: R
authors.lastname: Roy
authors.affiliation: Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
authors.forename: Danielle
authors.initials: D
authors.lastname: Durie
authors.affiliation: Department of Biochemistry, Wuhan University, Wuhan, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Biochemistry, Wuhan University, Wuhan, China.
authors.forename: Bing-Qian
authors.initials: BQ
authors.lastname: Liu
authors.affiliation: Protein Analysis and Proteomics Laboratory, London Research Institute, South Mimms, EN6 3LD, UK.
authors.forename: John Mark
authors.initials: JM
authors.lastname: Skehel
authors.affiliation: Department of Histopathology, Hammersmith Hospital Campus, Imperial College, London W120NN, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Mauri
authors.affiliation: Department of Histopathology, S. Chiara Hospital, Trento, Italy.
authors.forename: Lucia Veronica
authors.initials: LV
authors.lastname: Cuorvo
authors.affiliation: Department of Histopathology, S. Chiara Hospital, Trento, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Barbareschi
authors.affiliation: Department of Biochemistry, Wuhan University, Wuhan, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Guo
authors.affiliation: Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Holcik
authors.affiliation: Division of Cancer, Department of Surgery and Cancer, 1st Floor, ICTEM Building, Hammersmith Hospitals Campus of Imperial College London, Du Cane Road, London W12 0NN, UK o.pardo@imperial.ac.uk.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Seckl
authors.affiliation: Division of Cancer, Department of Surgery and Cancer, 1st Floor, ICTEM Building, Hammersmith Hospitals Campus of Imperial College London, Du Cane Road, London W12 0NN, UK.
authors.forename: Olivier E
authors.initials: OE
authors.lastname: Pardo
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D021581:Active Transport, Cell Nucleus; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000378:metabolism*; D006801:Humans; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D015398:Signal Transduction; D058207:Sumoylation; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D048948:14-3-3 Proteins; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D012333:RNA, Messenger; D051636:X-Linked Inhibitor of Apoptosis Protein; D051020:bcl-X Protein; C000619656:hnRNPA1 protein, human; D016222:Fibroblast Growth Factor 2; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3