Together, these data suggest that loss of MAP3K2 activity through depletion of the full-length protein or inhibiting its methylation at K260 phenocopies disruption of SMYD3’s catalytic activity, which is likely driven by overactivation of MAP3K2 and increased ERK1/2 activation to promote aggressive properties of PCa cells. Here, MAP3K2 is linked to posterior cortical atrophy.