A nuclear export signal and oxidative stress regulate ShcD subcellular localisation: A potential role for ShcD in the nucleus

作者：Ahmed Samrein B M; Prigent Sally A^*

来源：Cellular Signalling, 2014, 26(1): 32-40.

DOI：10.1016/j.cellsig.2013.09.003

• Shc
• Signalling adaptor
• Nuclear export signal
• Oxidative stress

Tumour cells alter their gene expression profile to acquire a more invasive and resistant phenotype. Overexpression of the signalling adaptor protein ShcD in melanoma was found to be a prerequisite for melanoma migration and invasion. In common with other Shc proteins, ShcD has been shown to be involved in coupling receptor tyrosine kinases to the Ras-mitogen activated protein kinase signalling pathway, and to have a predominant cytoplasmic distribution. Here we report that ShcD can exist within the nucleus, and show that its CH2 domain has a critical role in nuclear export of ShcD. Analysis of GFP-tagged ShcD mutants containing deletions or amino acid substitutions within the CH2 domain revealed (LCTLIPRM90)-L-83 as a functional nuclear export signal. We have further demonstrated that ShcD accumulates in the nucleus upon hydrogen peroxide treatment in FIAG-ShcD expressing HEK293 cells, as well as 518.A2 melanoma cells. Cross linking experiments showed that a proportion of ShcD is associated with DNA. Moreover we have shown that ShcD fused to the GAL4 DNA binding domain can drive transcription of a GAL4 site-driven luciferase reporter, suggesting a role for ShcD in regulating gene transcription. We suggest that ShcD nuclear translocation might provide melanoma cells with a mechanism that enables them to resist DNA damage due to oxidative stress.

• 出版日期2014-1