A mechanistic study showed that the ERK2 Thr188 mutation did not alter the phosphorylation of cytosolic substrates of ERK1/2 but dramatically changed the phosphorylation of its nuclear targets, suggesting that autophosphorylation at Thr188 promotes ERK2 nuclear translocation.54 In contrast, cardiomyocyte-specific activation of MEK5-ERK5 led to lethal dilated cardiomyopathy. The gene discussed is MAPK1; the disease is dilated cardiomyopathy.