A kinase-deficient TrkC receptor isoform activates Arf6-Rac1 signaling through the scaffold protein tamalin.
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.
Esteban
Pedro F
PF
Neural Development Group, Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD 21702, USA.
Yoon
Hye-Young
HY
Becker
Jodi
J
Dorsey
Susan G
SG
Caprari
Paola
P
Palko
Mary Ellen
ME
Coppola
Vincenzo
V
Saragovi
H Uri
HU
Randazzo
Paul A
PA
Tessarollo
Lino
L
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*
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