Slitrk5 Mediates BDNF-Dependent TrkB Receptor Trafficking and Signaling.

TitleSlitrk5 Mediates BDNF-Dependent TrkB Receptor Trafficking and Signaling.
Publication TypeJournal Article
Year of Publication2015
AuthorsSong M, Giza J, Proenca CC, Jing D, Elliott M, Dincheva I, Shmelkov SV, Kim J, Schreiner R, Huang S-H, Castrén E, Prekeris R, Hempstead BL, Chao MV, Dictenberg JB, Rafii S, Chen Z-Y, Rodriguez-Boulan E, Lee FS
JournalDev Cell
Volume33
Issue6
Pagination690-702
Date Published2015 Jun 22
ISSN1878-1551
KeywordsAnimals, Brain-Derived Neurotrophic Factor, Corpus Striatum, Endosomes, HEK293 Cells, Humans, Membrane Proteins, Mice, Mice, Knockout, Nerve Tissue Proteins, Neurons, Protein Binding, Protein Transport, rab GTP-Binding Proteins, Receptor, trkB, Receptor-Like Protein Tyrosine Phosphatases, Class 2, Signal Transduction
Abstract

Recent studies in humans and in genetic mouse models have identified Slit- and NTRK-like family (Slitrks) as candidate genes for neuropsychiatric disorders. All Slitrk isotypes are highly expressed in the CNS, where they mediate neurite outgrowth, synaptogenesis, and neuronal survival. However, the molecular mechanisms underlying these functions are not known. Here, we report that Slitrk5 modulates brain-derived neurotrophic factor (BDNF)-dependent biological responses through direct interaction with TrkB receptors. Under basal conditions, Slitrk5 interacts primarily with a transsynaptic binding partner, protein tyrosine phosphatase δ (PTPδ); however, upon BDNF stimulation, Slitrk5 shifts to cis-interactions with TrkB. In the absence of Slitrk5, TrkB has a reduced rate of ligand-dependent recycling and altered responsiveness to BDNF treatment. Structured illumination microscopy revealed that Slitrk5 mediates optimal targeting of TrkB receptors to Rab11-positive recycling endosomes through recruitment of a Rab11 effector protein, Rab11-FIP3. Thus, Slitrk5 acts as a TrkB co-receptor that mediates its BDNF-dependent trafficking and signaling.

DOI10.1016/j.devcel.2015.04.009
Alternate JournalDev. Cell
PubMed ID26004511
PubMed Central IDPMC4784688
Grant ListMH079513 / MH / NIMH NIH HHS / United States
R01 GM034107 / GM / NIGMS NIH HHS / United States
5UL1TR000457 / TR / NCATS NIH HHS / United States
P50 MH079513 / MH / NIMH NIH HHS / United States
RC1 AI080309 / AI / NIAID NIH HHS / United States
R01 NS052819 / NS / NINDS NIH HHS / United States
R01 EY008538 / EY / NEI NIH HHS / United States
GM804302 / GM / NIGMS NIH HHS / United States
R01 HL097797 / HL / NHLBI NIH HHS / United States
R01 NS030687 / NS / NINDS NIH HHS / United States
AI080309 / AI / NIAID NIH HHS / United States
HL097797 / HL / NHLBI NIH HHS / United States
NS052819 / NS / NINDS NIH HHS / United States
HL66592 / HL / NHLBI NIH HHS / United States
NS030687 / NS / NINDS NIH HHS / United States
UL1 TR000457 / TR / NCATS NIH HHS / United States