Endosomal Receptor Trafficking and Signal Transduction in Schwann cells: Regulation of the Nrg1-induced PI3-kinase pathway

Neuregulin1-ErbB signaling is important for various functions during Schwann cell development and myelination. Activation of the ErbB receptors also triggers myelin breakdown in mature myelinating Schwann cells. The mechanism by which the activated ErbB receptor complex elicits multiple biological functions in Schwann cells is unclear. In Charcot-Marie-Tooth (CMT) disease-the most common demyelinating neuropathy in the peripheral nervous system-many proteins involved in regulating intracellular vesicular trafficking and sorting through the endocytic pathway are found mutated. Endocytic pathways are also strongly implicated in the regulation of signal transduction by cell surface receptors. It is possible that aberrant regulation of the ErbB receptors and downstream signal activation by the impaired endocytic components contribute to the disease manifestation. The function of ErbB receptor trafficking and signal modulation in Schwann cells is largely unknown. We hypothesized that Nrg1-induced ErbB2 and ErbB3 receptor trafficking can differentially regulate signaling by spatially and temporally localizing receptors in different endocytic compartments. In this study, we show that following treatment with soluble Nrg1, internalized ErbB receptors are sorted iii into the late endosome/lysosome for degradation or transported to the recycling endosome and reappear on the cell surface. ErbB receptor recycling is also regulated by Nrg1 dose. Inhibition of receptor endocytosis by impairing dynamin activity blocked the Nrg1-induced Akt activation and abrogated the pro-myelinating effect in co-cultures.