ABSTRACT Growing evidence indicates a critical role of ubiquitin‐proteosome system in apoptosis regulation. A cardioprotective effect of ubiquitin (Ub) ligase of the C terminus of Hsc70‐interacting protein (CHIP) on myocytes has been reported. In the current study, we found that the cardioprotective effect of insulin growth factor‐1 (IGF‐1) was mediated by ERK5‐CHIP signal module via inducible cAMP early repressor (ICER) destabilization. In vitro runoff assay and Ub assay showed ICER as a substrate of CHIP Ub ligase. Both disruption of ERK5‐CHIP binding with inhibitory helical linker domain fragment (aa 101–200) of CHIP and the depletion of ERK5 by siRNA inhibited CHIP Ub ligase activity, which suggests an obligatory role of ERK5 on CHIP activation. Depletion of CHIP, using siRNA, inhibited IGF‐1‐mediated reduction of isoprot‐erenol‐mediated ICER induction and apoptosis. In diabetic mice subjected to myocardial infarction, the CHIP Ub ligase activity was decreased, with an increase in ICER expression. These changes were attenuated significantly in a cardiac‐specific constitutively active form of MEK5α transgenic mice (CA‐MEK5α‐Tg) previously shown to have greater functional recovery. Furthermore, pressure overload‐mediated ICER induction was enhanced in heterozygous CHIP +/_ mice. We identified ICER as a novel CHIP substrate and that the ERK5‐CHIP complex plays an obligatory role in inhibition of ICER expression, cardiomyocyte apoptosis, and cardiac dysfunction.—Woo, C.‐H., Le, N.‐T., Shishido, T., Chang, E., Lee, H., Heo, K.‐S., Mickelsen, D. M., Lu, Y., McClain, C., Spangenberg, T., Yan, C., Molina, C. A., Yang, J., Patterson, C., Abe, J.‐I. Novel role of C terminus of Hsc70‐interacting protein (CHIP) ubiquitin ligase on inhibiting cardiac apoptosis and dysfunction via regulating ERK5‐mediated degradation of inducible cAMP early repressor. FASEB J. 24, 4917–4928 (2010). www.fasebj.org