Interplay between Cell Migration and Neurite Outgrowth Determines SH2B1β-Enhanced Neurite Regeneration of Differentiated PC12 Cells

Chia-Ling Wu,Nan-Yuan Teng,Yu-Jung Chang,Yu-Han Chou,Linyi Chen,Hsin-Ling Hsu,Laszlo Buday

doi:10.1371/journal.pone.0034999

Chia-Ling Wu, Nan-Yuan Teng + Show 5 more

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https://doi.org/10.1371/journal.pone.0034999

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Abstract

The regulation of neurite outgrowth is crucial in developing strategies to promote neurite regeneration after nerve injury and in degenerative diseases. In this study, we demonstrate that overexpression of an adaptor/scaffolding protein SH2B1β promotes neurite re-growth of differentiated PC12 cells, an established neuronal model, using wound healing (scraping) assays. Cell migration and the subsequent remodeling are crucial determinants during neurite regeneration. We provide evidence suggesting that overexpressing SH2B1β enhances protein kinase C (PKC)-dependent cell migration and phosphatidylinositol 3-kinase (PI3K)-AKT-, mitogen activated protein kinase (MAPK)/extracellular signal-regulated protein kinase (ERK) kinase (MEK)-ERK-dependent neurite re-growth. Our results further reveal a cross-talk between pathways involving PKC and ERK1/2 in regulating neurite re-growth and cell migration. We conclude that temporal regulation of cell migration and neurite outgrowth by SH2B1β contributes to the enhanced regeneration of differentiated PC12 cells.

Highlights

Neuronal injury and degeneration are responsible for various neurological diseases
A study showed that mitogen activated protein kinase (MAPK)/extracellular signal-regulated protein kinase (ERK) kinase (MEK) kinase 1 (MEKK1) controls neurite re-growth by balancing ERK1/2 and JNK2 signaling after experimental injury [9]
We demonstrated that overexpression of a signaling adaptor protein SH2B1b promotes neurite regeneration of differentiated PC12 cells

Summary

Introduction

Neuronal injury and degeneration are responsible for various neurological diseases. The limited regeneration capacity restricts the recovery of neuronal damage. A study showed that mitogen activated protein kinase (MAPK)/ERK kinase (MEK) kinase 1 (MEKK1) controls neurite re-growth by balancing ERK1/2 and JNK2 signaling after experimental injury [9]. These studies suggest that activation of JNK and ERK and their interaction with the dynein/dynactin retrograde molecular motors is required for regeneration [1,5,7]. Overexpression of constitutively activated AKT has been shown to protect motor neurons from injury-induced cell death and promotes axonal regeneration [10,11]. By intraperitoneally administrating vanadium compounds to stimulate the activation of phosphatidylinositol

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