TAG1 Regulates the Endocytic Trafficking and Signaling of the Semaphorin3A Receptor Complex

Centre for Membrane Interactions and Dynamics, Department of Biomedical Science, University of Sheffield, Western Bank, Sheffield S10 2TN, United Kingdom.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 07/2012; 32(30):10370-82. DOI: 10.1523/JNEUROSCI.5874-11.2012
Source: PubMed


Endocytic trafficking of membrane proteins is essential for neuronal structure and function. We show that Transient Axonal Glycoprotein 1 (TAG1 or CNTN2), a contactin-related adhesion molecule, plays a central role in the differential trafficking of components of the semaphorin3A (Sema3A) receptor complex into distinct endosomal compartments in murine spinal sensory neuron growth cones. The semaphorin3A receptor is composed of Neuropilin1 (NRP1), PlexinA4, and L1, with NRP1 being the ligand-binding component. TAG1 interacts with NRP1, causing a change in its association with L1 in the Sema3A response such that L1 is lost from the complex following Sema3A binding. Initially, however, L1 and NRP1 endocytose together and only become separated intracellularly, with NRP1 becoming associated with endosomes enriched in lipid rafts and colocalizing with TAG1 and PlexinA4. When TAG1 is missing, NRP1 and L1 fail to separate and NRP1 does not become raft associated; colocalization with PlexinA4 is reduced and Plexin signaling is not initiated. These observations identify a novel role for TAG1 in modulating the intracellular sorting of signaling receptor complexes.

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    • "Furthermore, endocytosis, receptor phosphorylation, membrane protein shedding, intracellular protein degradation and protein transport have been identified as strategies to control semaphorin signalling at specific times and places in the cell (e.g. Dang et al., 2012; Nawabi et al., 2010; Yang and Terman, 2012; Zhu et al., 2007). "
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    • "It is found in the juxtanodal region, which is a key region of pathology in inflammatory neuropathy (Pollard and Armati, 2011). It also has a role in endocytosis (Dang et al., 2012). There are no studies of TAG-1 in GBS. "
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    • "Presently, the mechanism of TAG-1 function in Sema5B signalling is unknown. Dang et al. (2012) have recently shown that TAG-1 regulates Sema3A signalling by differential endocytotic trafficking of components of the Sema3A receptor complex (Dang et al., 2012). Whether TAG-1 functions in a similar way for Sema5B signalling is not known. "
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