Bicaudal‐D1 regulates the intracellular sorting and signalling of neurotrophin receptors |
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| Authors: | Matthew R G Russell Krzysztof B Wicher Ian Rosewell Bradley Spencer‐Dene David Ish‐Horowicz Giampietro Schiavo |
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| Institution: | 1. Electron Microscopy Laboratory, Cancer Research UK London Research Institute, , London, UK;2. Developmental Genetics Laboratory, Cancer Research UK London Research Institute, , London, UK;3. Transgenic Services laboratory, Cancer Research UK London Research Institute, , London, UK;4. Experimental Histopathology Laboratory, Cancer Research UK London Research Institute, , London, UK;5. Molecular NeuroPathobiology Laboratory, Cancer Research UK London Research Institute, , London, UK;6. Sobell Department of Motor Neuroscience & Movement Disorders, UCL‐Institute of Neurology, University College London, , London, UK |
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| Abstract: | We have identified a new function for the dynein adaptor Bicaudal D homolog 1 (BICD1) by screening a siRNA library for genes affecting the dynamics of neurotrophin receptor‐containing endosomes in motor neurons (MNs). Depleting BICD1 increased the intracellular accumulation of brain‐derived neurotrophic factor (BDNF)‐activated TrkB and p75 neurotrophin receptor (p75NTR) 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 TrkB isoforms and p75NTR 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 BICD1 regulates neurotrophin signalling by modulating the endosomal sorting of internalised ligand‐activated receptors. |
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| Keywords: | Bicd1 intracellular sorting neurotrophin signalling p75NTR TrkB |
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