Mitogen-activated protein kinase (MAPK) signaling pathways involve closely related MAP kinases, including extracellular-signal-related kinase 3 (ERK 3, also designated PRKM6 and p97MAPK). Serum, growth factors and phorbol esters can initiate ERK 3 signaling pathways. Despite lacking a definitive nuclear localization sequence, ERK 3 constitutively localizes to the nucleus upon activation. p38 pathway activation-dependent upregulation of ERK 3 is independent of the status of p53, Bcl-2 and caspase-3 during cell stress and damage induced by proteasome inhibition, suggesting ERK 3 in part mediates intracellular defense or cell rescue. The human ERK 3 gene maps to chromosome 15q21.2 and encodes a 721 amino acid protein.