# p66Shc deletion confers apoptotic resistance to loss of EGFR-ERK signalling in neural stem cells

## TL;DR

Deleting p66Shc in neural stem cells makes them resistant to cell death when growth factor signaling is blocked, which could be important for treating brain diseases or cancers.

## Contribution

This study reveals that p66Shc is a key regulator of apoptosis in neural stem cells under disrupted EGFR-ERK signaling.

## Key findings

- p66Shc knockout NSCs resist apoptosis caused by EGF withdrawal and EGFR-ERK inhibition.
- p66KO NSCs can differentiate into neurons even with prolonged MEK inhibition.
- p66Shc may serve as a target in neurodegenerative diseases or NSC-like cancers.

## Abstract

Growth factor signalling, through epidermal growth factor (EGF) and its receptor (EGFR), governs neural stem cell (NSC) proliferation, differentiation, and survival. The Src Homology and Collagen (SHC1) adaptor protein mediates EGFR survival-signalling in NSCs via its two shorter isoforms. However, the role of its longest isoform, p66Shc, in NSCs remains unclear. In this study, we investigated the role of p66Shc in NSC apoptosis by generating p66Shc knockout (p66KO) NSCs and assessing their responses to EGF withdrawal, EGFR inhibition, and MEK inhibition. We found that p66KO NSCs resisted apoptosis induced by EGF deprivation and EGFR-ERK pathway inhibition. In contrast, p66KO NSCs maintained their sensitivity to staurosporine, a general apoptosis inducer. Furthermore, p66KO NSCs subjected to prolonged MEK inhibition continued to differentiate into neurons, demonstrating their ability to evade apoptosis and progress through neuronal differentiation. These findings identify p66Shc as a pivotal regulator of NSC apoptosis in response to disrupted EGFR-ERK signalling. The ability of p66KO NSCs to resist apoptosis and differentiate without EGFR-ERK signalling highlights the potential of targeting p66Shc in conditions where growth factor signalling is disrupted, such as neurodegenerative diseases or brain injuries. Additionally, the role of p66Shc in modulating survival pathways may have broader implications for NSC-like cancers, where assessing p66Shc levels could provide prognostic value for the sensitivity of cancers to EGFR- or MEK-inhibition-based chemotherapies.