title: Signaling switch of the urotensin II vasosactive peptide GPCR: prototypic chemotaxic mechanism in glioma.
abstract: Multiform glioblastomas (GBM) are the most frequent and aggressive primary brain tumors in adults. The poor prognosis is due to neo-angiogenesis and cellular invasion, processes that require complex chemotaxic mechanisms involving motility, migration and adhesion. Understanding these different cellular events implies identifying receptors and transduction pathways that lead to and promote either migration or adhesion. Here we establish that glioma express the vasoactive peptide urotensin II (UII) and its receptor UT and that UT-mediated signaling cascades are involved in glioma cell migration and adhesion. Components of the urotensinergic systems, UII and UT, are widely expressed in patient-derived GBM tissue sections, glioma cell lines and fresh biopsy explants. Interestingly, gradient concentrations of UII produced chemoattracting migratory/motility effects in glioma as well as HEK293 cells expressing human UT. These effects mainly involved the G13/Rho/rho kinase pathway while partially requiring Gi/o/PI3K components. In contrast, we observed that homogeneous concentrations of UII drastically blocked cell motility and stimulated cell-matrix adhesions through a UT/Gi/o signaling cascade, partially involving phosphatidylinositol-3 kinase. Finally, we provide evidence that, in glioma cells, homogeneous concentration of UII allowed translocation of Gα13 to the UT receptor at the plasma membrane and increased actin stress fibers, lamellipodia formation and vinculin-stained focal adhesions. UII also provoked a re-localization of UT precoupled to Gαi in filipodia and initiated integrin-stained focal points. Altogether, these findings suggest that UT behaves as a chemotaxic receptor, relaying a signaling switch between directional migration and cell adhesion under gradient or homogeneous concentrations, thereby redefining sequential mechanisms affecting tumor cells during glioma invasion. Taken together, our results allow us to propose a model in order to improve the design of compounds that demonstrate signaling bias for therapies that target specifically the Gi/o signaling pathway.
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, DC2N, Astrocyte and Vascular Niche, Biomedical Research Institute (IRIB), TC2N network, University of Rouen, Mont-Saint-Aignan, France.
authors.forename: C
authors.initials: C
authors.lastname: Lecointre
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, DC2N, Astrocyte and Vascular Niche, Biomedical Research Institute (IRIB), TC2N network, University of Rouen, Mont-Saint-Aignan, France.
authors.forename: L
authors.initials: L
authors.lastname: Desrues
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, DC2N, Astrocyte and Vascular Niche, Biomedical Research Institute (IRIB), TC2N network, University of Rouen, Mont-Saint-Aignan, France.
authors.forename: J E
authors.initials: JE
authors.lastname: Joubert
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, DC2N, Astrocyte and Vascular Niche, Biomedical Research Institute (IRIB), TC2N network, University of Rouen, Mont-Saint-Aignan, France.|Department of Pharmacology, Institut of Pharmacology, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Perzo
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, DC2N, Astrocyte and Vascular Niche, Biomedical Research Institute (IRIB), TC2N network, University of Rouen, Mont-Saint-Aignan, France.
authors.forename: P-O
authors.initials: PO
authors.lastname: Guichet
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, DC2N, Astrocyte and Vascular Niche, Biomedical Research Institute (IRIB), TC2N network, University of Rouen, Mont-Saint-Aignan, France.
authors.forename: V
authors.initials: V
authors.lastname: Le Joncour
authors.affiliation: Department of Pharmacology, Institut of Pharmacology, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, Canada.|IGF, Institut of Functional Genomic, CNRS UMR 5203, Inserm U661, University of Montpellier 1 and 2, Montpellier, France.
authors.forename: C
authors.initials: C
authors.lastname: Brulé
authors.affiliation: UMR CNRS 6214, Inserm 1083, Faculté de Médecine 3, Angers, France.
authors.forename: M
authors.initials: M
authors.lastname: Chabbert
authors.affiliation: Department of Pharmacology, Institut of Pharmacology, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Leduc
authors.affiliation: IGF, Institut of Functional Genomic, CNRS UMR 5203, Inserm U661, University of Montpellier 1 and 2, Montpellier, France.
authors.forename: L
authors.initials: L
authors.lastname: Prézeau
authors.affiliation: Service of Anatomocytopathology, CHU of Rouen, ERI28 Inserm, IRIB, Rouen, France.
authors.forename: A
authors.initials: A
authors.lastname: Laquerrière
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, DC2N, Astrocyte and Vascular Niche, Biomedical Research Institute (IRIB), TC2N network, University of Rouen, Mont-Saint-Aignan, France.|Service of Neurosurgery, CHU of Rouen, Rouen, France.
authors.forename: F
authors.initials: F
authors.lastname: Proust
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, DC2N, Astrocyte and Vascular Niche, Biomedical Research Institute (IRIB), TC2N network, University of Rouen, Mont-Saint-Aignan, France.
authors.forename: P
authors.initials: P
authors.lastname: Gandolfo
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, DC2N, Astrocyte and Vascular Niche, Biomedical Research Institute (IRIB), TC2N network, University of Rouen, Mont-Saint-Aignan, France.
authors.forename: F
authors.initials: F
authors.lastname: Morin
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, DC2N, Astrocyte and Vascular Niche, Biomedical Research Institute (IRIB), TC2N network, University of Rouen, Mont-Saint-Aignan, France.
authors.forename: H
authors.initials: H
authors.lastname: Castel
mesh_terms: D000199:Actins / Q000378:metabolism; D001706:Biopsy; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D002633:Chemotaxis; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D058105:Polymerization; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D014579:Urotensins / Q000378:metabolism*
chemical_list: D000199:Actins; D043562:Receptors, G-Protein-Coupled; D014579:Urotensins; C029677:urotensin II