title: Intracellular LINGO-1 negatively regulates Trk neurotrophin receptor signaling.
abstract: Neurotrophins, essential regulators of many aspects of neuronal differentiation and function, signal via four receptors, p75, TrkA, TrkB and TrkC. The three Trk paralogs are members of the LIG superfamily of membrane proteins, which share extracellular domains consisting of leucine-rich repeat and C2 Ig domains. Another LIG protein, LINGO-1 has been reported to bind and influence signaling of p75 as well as TrkA, TrkB and TrkC. Here we examine the manner in which LINGO-1 influences the function of TrkA, TrkB and TrkC. We report that Trk activation promotes Trk association with LINGO-1, and that this association promotes Trk degradation by a lysosomal mechanism. This mechanism resembles the mechanism by which another LIG protein, LRIG1, promotes lysosomal degradation of receptor tyrosine kinases such as the EGF receptor. We present evidence indicating that the Trk/LINGO-1 interaction occurs, in part, within recycling endosomes. We show that a mutant form of LINGO-1, with much of the extracellular domain deleted, has the capacity to enhance TrkA signaling in PC12 cells, possibly by acting as an inhibitor of Trk down-regulation by full length LINGO-1. We propose that LINGO-1 functions as a negative feedback regulator of signaling by cognate receptor tyrosine kinases including TrkA, TrkB and TrkC.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA; Mental Illness Research Education and Clinical Center, VA Medical Center, Seattle, WA 98108, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Meabon
authors.affiliation: Immusoft, Seattle, WA 98103, USA.
authors.forename: Rian
authors.initials: R
authors.lastname: de Laat
authors.affiliation: Department of Pharmacology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Katsuaki
authors.initials: K
authors.lastname: Ieguchi
authors.affiliation: Seattle Biomedical Research Institute, Seattle, WA 98109, USA.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Serbzhinsky
authors.affiliation: Department of Physiology & Biophysics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Hudson
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: B Russel
authors.initials: BR
authors.lastname: Huber
authors.affiliation: Department of Comparative Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Jesse C
authors.initials: JC
authors.lastname: Wiley
authors.affiliation: Department of Physiology & Biophysics, University of Washington, Seattle, WA 98195, USA. Electronic address: mab@u.washington.edu.
authors.forename: Mark
authors.initials: M
authors.lastname: Bothwell
mesh_terms: D000818:Animals; D003593:Cytoplasm / Q000378:metabolism; D015536:Down-Regulation; D011992:Endosomes / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism*; D020813:Receptor, trkB / Q000378:metabolism*; D020812:Receptor, trkC / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*
chemical_list: C525164:LINGO1 protein, rat; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D020917:Receptor, trkA; D020813:Receptor, trkB; D020812:Receptor, trkC
keywords: LINGO-1; LRRN6a; Linx; TrkA; TrkB; TrkC