Intracellular LINGO-1 negatively regulates Trk neurotrophin receptor signaling
| Autor: | B. Russel Huber, Rian de Laat, Jesse C. Wiley, Dmitry Serbzhinsky, James S. Meabon, Katsuaki Ieguchi, Mark P. Hudson, Mark Bothwell |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Cytoplasm animal structures Down-Regulation Nerve Tissue Proteins Tropomyosin receptor kinase B Endosomes Tropomyosin receptor kinase A Tropomyosin receptor kinase C PC12 Cells Receptor tyrosine kinase Article 03 medical and health sciences Cellular and Molecular Neuroscience Low-affinity nerve growth factor receptor Animals Receptor trkB Receptor trkC Phosphorylation Receptor trkA Molecular Biology biology Membrane Proteins Cell Biology Cell biology Rats 030104 developmental biology nervous system Trk receptor embryonic structures biology.protein Signal transduction Lysosomes Neurotrophin Signal Transduction |
| Zdroj: | Molecular and cellular neurosciences. 70 |
| ISSN: | 1095-9327 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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