title: Mitogen-activated protein kinase-interacting kinase regulates mTOR/AKT signaling and controls the serine/arginine-rich protein kinase-responsive type 1 internal ribosome entry site-mediated translation and viral oncolysis.
abstract: Translation machinery is a major recipient of the principal mitogenic signaling networks involving Raf-ERK1/2 and phosphoinositol 3-kinase (PI3K)-mechanistic target of rapamycin (mTOR). Picornavirus internal ribosomal entry site (IRES)-mediated translation and cytopathogenic effects are susceptible to the status of such signaling cascades in host cells. We determined that tumor-specific cytotoxicity of the poliovirus/rhinovirus chimera PVSRIPO is facilitated by Raf-ERK1/2 signals to the mitogen-activated protein kinase (MAPK)-interacting kinase (MNK) and its effects on the partitioning/activity of the Ser/Arg (SR)-rich protein kinase (SRPK) (M. C. Brown, J. D. Bryant, E. Y. Dobrikova, M. Shveygert, S. S. Bradrick, V. Chandramohan, D. D. Bigner, and M, Gromeier, J. Virol. 22:13135-13148, 2014, doi:http://dx.doi.org/10.1128/JVI.01883-14). Here, we show that MNK regulates SRPK via mTOR and AKT. Our investigations revealed a MNK-controlled mechanism acting on mTORC2-AKT. The resulting suppression of AKT signaling attenuates SRPK activity to enhance picornavirus type 1 IRES translation and favor PVSRIPO tumor cell toxicity and killing.
  
  
  OBJECTIVE
  Oncolytic immunotherapy with PVSRIPO, the type 1 live-attenuated poliovirus (PV) (Sabin) vaccine containing a human rhinovirus type 2 (HRV2) IRES, is demonstrating early promise in clinical trials with intratumoral infusion in recurrent glioblastoma (GBM). Our investigations demonstrate that the core mechanistic principle of PVSRIPO, tumor-selective translation and cytotoxicity, relies on constitutive ERK1/2-MNK signals that counteract the deleterious effects of runaway AKT-SRPK activity in malignancy.
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA Department of Surgery, Division of Neurosurgery, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Brown
authors.affiliation: Department of Surgery, Division of Neurosurgery, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Mikhail I
authors.initials: MI
authors.lastname: Dobrikov
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA Department of Surgery, Division of Neurosurgery, Duke University Medical Center, Durham, North Carolina, USA grome001@mc.duke.edu.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gromeier
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D050504:Oncolytic Viruses / Q000235:genetics / Q000254:growth & development*; D017955:Poliovirus / Q000235:genetics / Q000254:growth & development; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012229:Rhinovirus / Q000235:genetics / Q000254:growth & development; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; C491395:MKNK1 protein, human; C087728:SRPK1 protein, human; D000076225:Mechanistic Target of Rapamycin Complex 2; D051058:Oncogene Protein v-akt; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases