Fig. 4.

The primary structure of ERK5 and its regulation. ERK5, also called a big MAP kinase, is twice the size of other MAPKs and hence the largest kinase within its group. It possesses a catalytic N-terminus domain including the MAPK-conserved threonine/glutamic acid/tyrosine (TEY) motif in the activation loop with 50% homology with ERK1/2, and a unique C-terminus tail with transactivation domains. The activation of ERK5 occurs via interaction with and dual phosphorylation in its TEY motif by MEK. On the other hand, inflammatory stimuli or athero-prone flow (d-flow) leads to ERK5 deactivation via phosphorylation of Ser486 or Ser496, respectively. SUMO modification of the N-terminus K6 and K22 sites inhibit its own transactivation. B. Insulin growth factor-1 (IGF-1) or pre-conditioning activates ERK5 kinase activity in cardiomyocytes, leading to phosphorylation of the TEY motif and de-SUMOylation of the two sites which then fully activates ERK5 transcriptional activity. In contrast, ischemia under the diabetic condition (DM + MI), reactive oxygen species (ROS), and advanced glycation endo-products (AGE) increase ERK5 SUMOylation and ERK5 Ser496 phosphorylation, inhibiting ERK5 transcriptional activity and promoting ERK5 degradation via ERK5 Ser486 phosphorylation. CHIP; carboxyl terminus of HSP70-interacting protein, p90RSK: p90 ribosomal S6 kinase; PKCζ, protein kinase C-ζ; and PPARs, peroxisome proliferator-activated receptors. Adapted, reprinted, and modified from Heo et al. [22] with permission from Antioxidants and Redox Signaling, April 2016, published by Mary Ann Liebert, Inc., New Rochelle, NY.