Dual action of epidermal growth factor: extracellular signal-stimulated nuclear-cytoplasmic export and coordinated translation of selected messenger RNA.
We report the first example of a coordinated dual action of epidermal growth factor (EGF) in stimulating the nuclear-cytoplasmic export and translation of a select messenger RNA (mRNA). The effect of EGF is mediated by the RNA-binding protein Grb7 (growth factor receptor-bound protein 7), which serves as an adaptor for a specific mRNA-protein export complex and a translational regulator. Using the kappa-opioid receptor (OR [KOR]) as a model, we demonstrate that EGF activates nuclear SHP-2 (Src homology region 2-containing tyrosine phosphatase), which dephosphorylates Grb7 in the nucleus. Hypophosphorylated Grb7 binds to the KOR mRNA and recruits the Hu antigen R-exportin-1 (CRM1) complex to form a nuclear-cytoplasmic export complex that exports KOR mRNA. EGF also activates focal adhesion kinase in the cytoplasm to rephosphorylate Grb7, releasing KOR mRNA for active translation. In summary, this study uncovers a coordinated, dual activity of EGF in facilitating nuclear export of a specific mRNA-protein complex as well as translational activation of the exported mRNA.
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455.
Nien-Pei
NP
Tsai
Ya-Lun
YL
Lin
Yao-Chen
YC
Tsui
Li-Na
LN
Wei
D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D051382:GRB7 Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D028884:Karyopherins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000096:biosynthesis* / Q000235:genetics; D000097606:Exportin 1 Protein
D004815:Epidermal Growth Factor; D051417:Focal Adhesion Kinase 1; D051382:GRB7 Adaptor Protein; D028884:Karyopherins; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D017473:Receptors, Opioid, kappa; D000097606:Exportin 1 Protein; C495957:Grb7 protein, rat; C496052:Ptk2 protein, rat