title: A kinase-deficient TrkC receptor isoform activates Arf6-Rac1 signaling through the scaffold protein tamalin.
abstract: Neurotrophins play an essential role in mammalian development. Most of their functions have been attributed to activation of the kinase-active Trk receptors and the p75 neurotrophin receptor. Truncated Trk receptor isoforms lacking the kinase domain are abundantly expressed during development and in the adult; however, their function and signaling capacity is largely unknown. We show that the neurotrophin-3 (NT3) TrkCT1-truncated receptor binds to the scaffold protein tamalin in a ligand-dependent manner. Moreover, NT3 initiation of this complex leads to activation of the Rac1 GTPase through adenosine diphosphate-ribosylation factor 6 (Arf6). At the cellular level, NT3 binding to TrkCT1-tamalin induces Arf6 translocation to the membrane, which in turn causes membrane ruffling and the formation of cellular protrusions. Thus, our data identify a new signaling pathway elicited by the kinase-deficient TrkCT1 receptor. Moreover, we establish NT3 as an upstream regulator of Arf6.
authors.affiliation: Neural Development Group, Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD 21702, USA.
authors.forename: Pedro F
authors.initials: PF
authors.lastname: Esteban
authors.forename: Hye-Young
authors.initials: HY
authors.lastname: Yoon
authors.forename: Jodi
authors.initials: J
authors.lastname: Becker
authors.forename: Susan G
authors.initials: SG
authors.lastname: Dorsey
authors.forename: Paola
authors.initials: P
authors.lastname: Caprari
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Palko
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Coppola
authors.forename: H Uri
authors.initials: HU
authors.lastname: Saragovi
authors.forename: Paul A
authors.initials: PA
authors.lastname: Randazzo
authors.forename: Lino
authors.initials: L
authors.lastname: Tessarollo
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008954:Models, Biological; D020033:Protein Isoforms / Q000502:physiology; D020812:Receptor, trkC / Q000502:physiology*; D015398:Signal Transduction; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D000089982:ADP-Ribosylation Factor 6; D002352:Carrier Proteins; D008565:Membrane Proteins; D020033:Protein Isoforms; C410230:tamalin protein, human; D020812:Receptor, trkC; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human; C000715727:Arf6 protein, mouse; D020830:rac1 GTP-Binding Protein