In L6E9 skeletal muscle cells ternary complex factor (TCF) Elk-1 expression increased with the onset of skeletal muscle differentiation, whereas its activation decreased as a function of differentiation. Its expression was predominantly restricted to cytoplasm and activated ones were predominantly restricted to the nucleus of the differentiated cells. Inhibition of ERK-1/-2 activities by PD098059 resulted into significant reduction in Elk-1 expression and phosphorylation during differentiation. In contrast, inhibition of p38 mitogen-activated protein kinase (MAPK) enhanced Elk-1 expression and activation, thereby mediating inhibition of skeletal muscle differentiation. Overexpression of inactive mutant Elk-1 enhanced differentiation. Data suggest that ERK-1/-2 and p38 MAPK activities modulate Elk-1 expression and activation to regulate skeletal muscle differentiation.