title: Slitrk5 Mediates BDNF-Dependent TrkB Receptor Trafficking and Signaling.
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.
authors.affiliation: Department of Psychiatry, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA.
authors.forename: Minseok
authors.initials: M
authors.lastname: Song
authors.affiliation: Department of Psychiatry, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA.
authors.forename: Joanna
authors.initials: J
authors.lastname: Giza
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
authors.forename: Catia C
authors.initials: CC
authors.lastname: Proenca
authors.affiliation: Department of Psychiatry, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA.
authors.forename: Deqiang
authors.initials: D
authors.lastname: Jing
authors.affiliation: Department of Psychiatry, University of California at San Francisco, 600 16th Street, San Francisco, CA 94158, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Elliott
authors.affiliation: Department of Psychiatry, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA.
authors.forename: Iva
authors.initials: I
authors.lastname: Dincheva
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, Langone Medical Center, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA.
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Shmelkov
authors.affiliation: Department of Psychiatry, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA; Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
authors.forename: Jihye
authors.initials: J
authors.lastname: Kim
authors.affiliation: Dyson Vision Research Institute, Department of Ophthalmology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Schreiner
authors.affiliation: Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine and the Collaborative Innovation Center for Brain Science, Shandong University, No. 44 Wenhua Xi Road, Jinan, Shandong 250012, China.
authors.forename: Shu-Hong
authors.initials: SH
authors.lastname: Huang
authors.affiliation: Neuroscience Centre, University of Helsinki, 00790 Helsinki, Finland.
authors.forename: Eero
authors.initials: E
authors.lastname: Castrén
authors.affiliation: Department of Cell and Developmental Biology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Rytis
authors.initials: R
authors.lastname: Prekeris
authors.affiliation: Division of Hematology/Medical Oncology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA.
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Hempstead
authors.affiliation: Molecular Neurobiology Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA.
authors.forename: Moses V
authors.initials: MV
authors.lastname: Chao
authors.affiliation: AccelBio, DMC Advanced Biotechnology Incubator, Brooklyn, NY 11226, USA; Department of Cell Biology, SUNY Downstate Medical School, 450 Clarkson Avenue, Brooklyn, NY 11203, USA.
authors.forename: Jason B
authors.initials: JB
authors.lastname: Dictenberg
authors.affiliation: Department of Genetic Medicine, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA.
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
authors.affiliation: Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine and the Collaborative Innovation Center for Brain Science, Shandong University, No. 44 Wenhua Xi Road, Jinan, Shandong 250012, China. Electronic address: zheyuchen@sdu.edu.cn.
authors.forename: Zhe-Yu
authors.initials: ZY
authors.lastname: Chen
authors.affiliation: Dyson Vision Research Institute, Department of Ophthalmology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA. Electronic address: boulan@med.cornell.edu.
authors.forename: Enrique
authors.initials: E
authors.lastname: Rodriguez-Boulan
authors.affiliation: Department of Psychiatry, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA; Department of Pharmacology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA.
authors.forename: Francis S
authors.initials: FS
authors.lastname: Lee
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D020813:Receptor, trkB / Q000378:metabolism*; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000378:metabolism; D015398:Signal Transduction; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000099193:rab11 GTP-Binding Proteins
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D020813:Receptor, trkB; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C550141:Slitrk5 protein, mouse