We show that activation of the H-Ras-MEK1-ERK1/2 pathway by hypertrophic stimuli promotes Bcl-xL-Ser14 phosphorylation, which disrupts the inhibitory interaction between Bcl-xL and IP3Rs, thereby augmenting SR Ca2+ release and activating the calcineurin-NFAT pathway, a major signaling mechanism controlling cardiac hypertrophy. The gene discussed is MAPK3; the disease is cardiac hypertrophy.