c-Src-mediated phosphorylation of hnRNP K drives translational activation of specifically silenced mRNAs.
hnRNPK and hnRNP E1/E2 mediate translational silencing of cellular and viral mRNAs in a differentiation-dependent way by binding to specific regulatory sequences. The translation of 15-lipoxygenase (LOX) mRNA in erythroid precursor cells and of the L2 mRNA of human papilloma virus type 16 (HPV-16) in squamous epithelial cells is silenced when either of these cells is immature and is activated in maturing cells by unknown mechanisms. Here we address the question of how the silenced mRNA can be translationally activated. We show that hnRNP K and the c-Src kinase specifically interact with each other, leading to c-Src activation and tyrosine phosphorylation of hnRNP K in vivo and in vitro. c-Src-mediated phosphorylation reversibly inhibits the binding of hnRNP K to the differentiation control element (DICE) of the LOX mRNA 3' untranslated region in vitro and specifically derepresses the translation of DICE-bearing mRNAs in vivo. Our results establish a novel role of c-Src kinase in translational gene regulation and reveal a mechanism by which silenced mRNAs can be translationally activated.
Ostareck-Lederer
Antje
A
European Molecular Biology Laboratory, Heidelberg, Germany. aostareck@anadyspharma.de
Ostareck
Dirk H
DH
Cans
Christophe
C
Neubauer
Gitte
G
Bomsztyk
Karol
K
Superti-Furga
Giulio
G
Hentze
Matthias W
MW
D020413:3' Untranslated Regions; D000595:Amino Acid Sequence; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism; D000081247:CSK Tyrosine-Protein Kinase; D020868:Gene Silencing; D006367:HeLa Cells; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger; D012261:Ribonucleoproteins / Q000235:genetics* / Q000378:metabolism; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism; D018909:src Homology Domains; D019061:src-Family Kinases
D020413:3' Untranslated Regions; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D012333:RNA, Messenger; D012261:Ribonucleoproteins; D014443:Tyrosine; D001093:Arachidonate 15-Lipoxygenase; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D010751:Phosphopyruvate Hydratase