Using this peptide-based strategy, we show that (i) the ERK-ERK interaction is a prerequisite for ERKT188-autophosphorylation which in turn is a central molecular event for nuclear ERK localization and signaling, (ii) ERKT188-phosphorylation is also upregulated in human colon and lung cancer, and (iii) interference with nuclear ERK signaling is a cardio-safe targeting strategy to prevent pathological ERK1/2 signaling in the heart and in tumor cells. Here, MAPK1 is linked to lung cancer.