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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.

Pubmed ID: 12052863

Authors

  • Ostareck-Lederer A
  • Ostareck DH
  • Cans C
  • Neubauer G
  • Bomsztyk K
  • Superti-Furga G
  • Hentze MW

Journal

Molecular and cellular biology

Publication Data

July 7, 2002

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK45978
  • Agency: NIGMS NIH HHS, Id: GM45134

Mesh Terms

  • 3' Untranslated Regions
  • Amino Acid Sequence
  • Arachidonate 15-Lipoxygenase
  • Gene Silencing
  • HeLa Cells
  • Heterogeneous-Nuclear Ribonucleoprotein K
  • Heterogeneous-Nuclear Ribonucleoproteins
  • Humans
  • Molecular Sequence Data
  • Mutation
  • Phosphopyruvate Hydratase
  • Phosphorylation
  • Protein Biosynthesis
  • Protein-Tyrosine Kinases
  • RNA, Messenger
  • Ribonucleoproteins
  • Tyrosine
  • src Homology Domains
  • src-Family Kinases