An intracellular protein kinase cascade containing at least ERK5 (also called BMK1; a MAPK), a MEK (a MAPKK) and a MAP3K. The cascade can also contain two additional tiers: the upstream MAP4K and the downstream MAP Kinase-activated kinase (MAPKAPK). The kinases in each tier phosphorylate and activate the kinases in the downstream tier to transmit a signal within a cell.