title: IGF2BP1 promotes cell migration by regulating MK5 and PTEN signaling.
abstract: In primary neurons, the oncofetal RNA-binding protein IGF2BP1 (IGF2 mRNA-binding protein 1) controls spatially restricted β-actin (ACTB) mRNA translation and modulates growth cone guidance. In cultured tumor-derived cells, IGF2BP1 was shown to regulate the formation of lamellipodia and invadopodia. However, how and via which target mRNAs IGF2BP1 controls the motility of tumor-derived cells has remained elusive. In this study, we reveal that IGF2BP1 promotes the velocity and directionality of tumor-derived cell migration by determining the cytoplasmic fate of two novel target mRNAs: MAPK4 and PTEN. Inhibition of MAPK4 mRNA translation by IGF2BP1 antagonizes MK5 activation and prevents phosphorylation of HSP27, which sequesters actin monomers available for F-actin polymerization. Consequently, HSP27-ACTB association is reduced, mobilizing cellular G-actin for polymerization in order to promote the velocity of cell migration. At the same time, stabilization of the PTEN mRNA by IGF2BP1 enhances PTEN expression and antagonizes PIP(3)-directed signaling. This enforces the directionality of cell migration in a RAC1-dependent manner by preventing additional lamellipodia from forming and sustaining cell polarization intrinsically. IGF2BP1 thus promotes the velocity and persistence of tumor cell migration by controlling the expression of signaling proteins. This fine-tunes and connects intracellular signaling networks in order to enhance actin dynamics and cell polarization.
authors.affiliation: Section for Molecular Cell Biology, Institute of Molecular Medicine, Martin Luther University of Halle, Halle, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Stöhr
authors.forename: Marcel
authors.initials: M
authors.lastname: Köhn
authors.forename: Marcell
authors.initials: M
authors.lastname: Lederer
authors.forename: Markus
authors.initials: M
authors.lastname: Glass
authors.forename: Claudia
authors.initials: C
authors.lastname: Reinke
authors.forename: Robert H
authors.initials: RH
authors.lastname: Singer
authors.forename: Stefan
authors.initials: S
authors.lastname: Hüttelmaier
mesh_terms: D000199:Actins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D016764:Cell Polarity / Q000502:physiology; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D018832:Molecular Chaperones; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000199:Actins; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D012333:RNA, Messenger; C111049:MAP-kinase-activated kinase 5; D017346:Protein Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human