Bicaudal‐ D 1 regulates the intracellular sorting and signalling of neurotrophin receptors
Bicaudal‐ D 1 regulates the intracellular sorting and signalling of neurotrophin receptors
Abstract We have identified a new function for the dynein adaptor Bicaudal D homolog 1 ( BICD 1) by screening a si RNA library for genes affecting the dynamics of neurotrophin receptor‐containing endosomes in motor neurons ( MN s). Depleting BICD 1 increased the intracellular accumulation of brain‐derived neurotrophic factor ( BDNF )‐activated T rk B and p75 neurotrophin receptor (p75 NTR ) by disrupting the endosomal sorting, reducing lysosomal degradation and increasing the co‐localisation of these neurotrophin receptors with retromer‐associated sorting nexin 1. The resulting re‐routing of active receptors increased their recycling to the plasma membrane and altered the repertoire of signalling‐competent T rk B isoforms and p75 NTR available for ligand binding on the neuronal surface. This resulted in attenuated, but more sustained, AKT activation in response to BDNF stimulation. These data, together with our observation that Bicd1 expression is restricted to the developing nervous system when neurotrophin receptor expression peaks, indicate that BICD 1 regulates neurotrophin signalling by modulating the endosomal sorting of internalised ligand‐activated receptors.
- University College London United Kingdom
- UCL Queen Square Institute of Neurology United Kingdom
- London Research Institute United Kingdom
- UNIVERSITY COLLEGE LONDON, Bartlett School of Planning United Kingdom
- Cancer Research UK United Kingdom
Bicd1, Blotting, Western, Fluorescent Antibody Technique, Endosomes, Receptors, Nerve Growth Factor, Real-Time Polymerase Chain Reaction, Models, Biological, Cell Line, p75NTR, Mice, Microscopy, Electron, Transmission, Animals, RNA, Small Interfering, Adaptor Proteins, Signal Transducing, Motor Neurons, Brain-Derived Neurotrophic Factor, TrkB, Immunohistochemistry, neurotrophin signalling, Cytoskeletal Proteins, Luminescent Proteins, Protein Transport, intracellular sorting, Signal Transduction, Red Fluorescent Protein
Bicd1, Blotting, Western, Fluorescent Antibody Technique, Endosomes, Receptors, Nerve Growth Factor, Real-Time Polymerase Chain Reaction, Models, Biological, Cell Line, p75NTR, Mice, Microscopy, Electron, Transmission, Animals, RNA, Small Interfering, Adaptor Proteins, Signal Transducing, Motor Neurons, Brain-Derived Neurotrophic Factor, TrkB, Immunohistochemistry, neurotrophin signalling, Cytoskeletal Proteins, Luminescent Proteins, Protein Transport, intracellular sorting, Signal Transduction, Red Fluorescent Protein
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