Dysregulation of ErbB Receptor Trafficking and Signaling in Demyelinating Charcot-Marie-Tooth Disease - PubMed (original) (raw)

Review

Dysregulation of ErbB Receptor Trafficking and Signaling in Demyelinating Charcot-Marie-Tooth Disease

Samuel M Lee et al. Mol Neurobiol. 2017 Jan.

Abstract

Charcot-Marie-Tooth (CMT) disease is the most common inherited peripheral neuropathy with the majority of cases involving demyelination of peripheral nerves. The pathogenic mechanisms of demyelinating CMT remain unclear, and no effective therapy currently exists for this disease. The discovery that mutations in different genes can cause a similar phenotype of demyelinating peripheral neuropathy raises the possibility that there may be convergent mechanisms leading to demyelinating CMT pathogenesis. Increasing evidence indicates that ErbB receptor-mediated signaling plays a major role in the control of Schwann cell-axon communication and myelination in the peripheral nervous system. Recent studies reveal that several demyelinating CMT-linked proteins are novel regulators of endocytic trafficking and/or phosphoinositide metabolism that may affect ErbB receptor signaling. Emerging data have begun to suggest that dysregulation of ErbB receptor trafficking and signaling in Schwann cells may represent a common pathogenic mechanism in multiple subtypes of demyelinating CMT. In this review, we focus on the roles of ErbB receptor trafficking and signaling in regulation of peripheral nerve myelination and discuss the emerging evidence supporting the potential involvement of altered ErbB receptor trafficking and signaling in demyelinating CMT pathogenesis and the possibility of modulating these trafficking and signaling processes for treating demyelinating peripheral neuropathy.

Keywords: Charcot-Marie-Tooth disease; Demyelination; Endocytic trafficking; ErbB receptor; Peripheral neuropathy.

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Conflict of interest statement

Compliance with Ethical Standard Conflict of Interest The authors declare that they have no conflict of interest.

Figures

Fig. 1

Fig. 1

ErbB receptor-mediated signaling in regulation of myelination. Binding of Nrg1 induces heterodimerization of ErbB2 and ErbB3 on Schwann cell surface and activation of the ErbB2/ErbB3 receptor, leading to activation of multiple downstream signaling pathways. Activated ErbB2/ErbB3 receptor stimulates class I PI3K to produce PI(3,4,5)P3 from PI(4,5)P2 (step 1), which activates Akt (step 3) signaling. This process is antagonized by PTEN which dephosphorylates PI(3,4,5)P3 back to PI(4,5)P2 (step 2). Activation of ErbB2/ErbB3 receptor also causes activation of Mek (step 4) and Erk (step 5) signaling. Endosomal PI(5)P production involves a series of reactions mediated by PI5K which produces PI(3,5)P2 from PI(3)P (step 6) and by MTMRs which convert PI(3,5)P2 to PI(5)P (step 7). The presence of PI(5)P promotes Akt signaling (step 8). In addition to the PI3K/Akt and Mek/Erk pathways, ErbB receptor also activates JNK1/c-Jun signaling (steps 9 and 10) and PLCγ/calcineurin signaling (steps 11 and 12). Together, these pathways regulate myelination and myelin maintenance

Fig. 2

Fig. 2

Proposed model of dysregulated ErbB receptor trafficking and signaling in demyelinating CMT. ErbB2 and ErbB3 proteins may undergo constitutive endocytosis in the absence of ligand (step 1) and then travel through recycling endosomes (step 2) back to the cell surface (step 3). Binding of Nrg1 triggers heterodimerization and activation of ErbB2/ErbB3 receptor, leading to activation of downstream signaling pathways at the plasma membrane (thunderbolt). Ligand binding also promotes ubiquitination (Ub) and endocytosis of ErbB receptors (step 4). The internalized ErbB receptors can still signal to their downstream effectors at the early endosome (thunderbolt). Ubiquitination of ErbB receptors may also occur at the early endosome. The ubiquitinated ErbB receptors are recognized and sorted at the early endosome by ESCRTs into intraluminal vesicles to form multivesicular bodies (step 5). Once inside the multivesicular bodies, ErbB receptors can no longer produce signaling output. As multivesicular bodies fuse with lysosomes, ErbB receptors are degraded and their signaling is completely terminated (step 6). Removal of ubiquitin signals from ErbB receptors at the early endosome by deubiquitinating enzymes (step 7) allows recycling of these receptors back to cell surface (steps 2 and 3). Mutations in proteins associated with various types of demyelinating CMT (shown in red) can affect endocytosis, endosome-to-lysosome trafficking, and endocytic recycling to cause demyelinating peripheral neuropathy. Specific phosphoinositides enriched in various membrane compartments are indicated by different colors as defined in the legend

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