The ERKs are a subfamily of the MAPKs that have been implicated in cell growth and differentiation. Extracellular signal-regulated kinase 8 (Erk8) is a large MAP kinase whose activity is controlled by serum and the c-Src non-receptor tyrosine kinase. ERK8 down-regulates transactivation of the glucocorticoid receptor through Hic-5 and can negatively regulate transcriptional co-activation of androgen receptor and GRalpha by Hic-5 in a kinase-independent manner, suggesting a broader role for ERK8 in the regulation of nuclear receptors beyond estrogen receptor alpha. Erk8 is a novel effector of RET/PTC3 and, therefore, RET biological functions.