We recently described the purification and cloning of extracellular signal-regulated kinase 1 (ERKl), which appears to play a pivotal role In converting tyrosine phosphorylation into the serlne/threonine phosphorylations that regulate downstream events. We now describe cloning and characterixation of two ERKlrelated kinases, ERK2 and ERW, and provide evidence suggesting that there are additional ERK family members. At least two of the ERKsare activated in response to growth factors; their activations correlate with tyrosine phophorylation, but also depend on additional modifications. Transcripts corresponding to the three cloned ERKs are distinctly regulated both in vivo and in a differentiating cell line. Thus, this family of kinases may serve as intermediates that depend on tyrosine phosphorylation to activate serine/threonine phosphorylation cascades. Individual family members may mediate responses in different developmental stages, in different cell types, or following exposure to differ-. ent extracellular signals.