Tyrosine Phosphorylation in the C-Terminal Nuclear Localization and Retention Signal (C-NLS)‎ of the EWS Protein

Abstract EN

Ewing sarcoma (EWS) proto-oncoprotein, an RNA-binding protein, is involved in DNA recombination and repair, gene expression, RNA processing and transport, as well as cell signalling.

Chimeric EWS oncoproteins generated by chromosomal translocations between EWSR1 and the genes of transcription factors cause malignant tumors.

To understand the loss of function by these translocations, the role of the intact EWS protein has to be investigated.

The predominantly nuclear localization of the EWS protein via a transportin-1-mediated mechanism is dependent on the recently identified C-NLS (also known as PY-NLS).

Among other residues in the C-NLS, Y656 interacts with transportin-1 and is essential for its nuclear localization.

Here, we show that Y656 is phosphorylated, which seems to be a critical factor for transportin-1-mediated nuclear import.

If Y656 was mutated cytosolic aggregates of the EWS protein, colocalized with transportin-1, were observed, similar to those described with mutants of the closely related FUS/TLS protein that had amino acid substitutions in the PY-NLS causing familial amyothrophic lateral sclerosis.