ORALS

MAPKs signaling proteins that regulate essentially all stimulated cellular processes. Dysregulation of these kinases is involved in many diseases such as cancer and inflammation. A hallmark of the MAPKs’ activity is their nuclear translocation, where they activate many targets including transcription factors and chromatin modifiers. The MAPKs do not use the canonical nuclear shuttling machinery, importin (Imp-α∙β/NLS). Rather, we elucidated the mechanism of stimulated nuclear translocation of ERK1/2 (ERK) that upon stimulation is phosphorylated on its nuclear translocation signal (NTS) that allow interaction with Imp7, that transfers ERK to the nucleus [1]. P38/JNK interact mainly with Imp9 (and to a lesser extent Imp7) that further binds Imp3 to escort these MAPKs to the nucleus  [2]. These mechanisms are very specific to the distinct MAPKs and serve as an unexplored level of transcriptional regulation, crucial for proliferation and differentiation. We identified the Imp7/kinase interaction and prepared peptides based on these sequences. These peptides (EPE for ERK and PERY for p38/JNK) competes out the binding, preventes nuclear translocation, as well as their nuclear and pathological effects [3,4]. The prevention of nuclear translocation in cancer and inflammation models, was more effective with less side effects than the MAPK inhibitors that are currently in clinical use or trials. We are now developing the aforementioned drugs into clinical use for melanoma, as well as pancreatic, colon and breast cancers. 

References:
[1] Chuderland, D.; Konson, A.; Seger, R. Identification and characterization of a general nuclear translocation signal in signaling proteins. Mol. Cell 2008, 31, 850-861.
[2] Zehorai, E.; Seger, R. Beta-Like Importins Mediate the Nuclear Translocation of MAPKs. Cell. Physiol. Biochem. 2019, 52, 802-821, doi:10.33594/000000056.
[3] Plotnikov, A.; Flores, K.; Maik-Rachline, G.; Zehorai, E.; Kapri-Pardes, E.; Berti, D.A.; Hanoch, T.; Besser, M.J.; Seger, R. The nuclear translocation of ERK1/2 as an anticancer target. Nat Commun 2015, 6, 6685, doi:10.1038/ncomms7685.
[4] Maik-Rachline, G.; Zehorai, E.; Hanoch, T.; Blenis, J.; Seger, R. The nuclear translocation of the kinases p38 and JNK promotes inflammation-induced cancer. Sci Signal 2018, 11, doi:10.1126/scisignal.aao3428.