The extracellular signal-regulated kinase 1 and 2 (ERK1/2) are central signaling proteins that regulate proliferation, differentiation, survival, and more. The predominant localization of ERK1/2 in quiescent cells is the cytoplasm, mostly due to their interaction with anchoring proteins. Stimulation of the cells releases ERK1/2 molecules from their anchors to allow their rapid nuclear translocation. Previous studies in our lab revealed that ERK1/2 translocation is mediated by a nuclear translocation signal (NTS) that contains two pSer residues that facilitate ERK1/2 binding to importin7 (Imp7, ref 1). The NTS is hindered by the anchoring proteins in quiescent cells, but the stimulated detachment uncovers it, and allows its phosphorylation by CK2 (2). Since the nuclear ERK1/2 is essential for the induction of proliferation, we hypothesized that this process can serve as a good target for anti-cancer therapy. Indeed, application of peptides derived from the NTS sequence conjugated to myristic acid inhibited the nuclear ERK1/2 translocation, and prevented phosphorylation of nuclear, but not cytoplasmic targets. Importantly, the peptides dramatically slowed down the proliferation rate of most transformed cells (particularly from melanoma) but had only minor effects on non-transformed cells. These results may serve as a proof of concept for the suitability of targeting the nuclear translocation of ERK1/2 as an anti cancer therapy.
References:
1. Chuderland et al. Mol Cell 2008
2. Plotnikov et al. Mol Cell Biol 2011