A regulatory role for p38δ MAPK in keratinocyte differentiation -: Evidence for p38δ-ERK1/2 complex formation

p38 MAPK isoforms are important in the regulation of a variety of cellular processes. Among the four described p38 isoforms, p38alpha, beta, and delta are expressed in keratinocytes (Dashti, S. R., Efimova, T., and Eckert, R. L. (2001) J. Biol. Chem. 276, 8059 - 8063). However, very little is known about how individual p38 isoforms regulate keratinocyte function. In the present study, we use okadaic acid (OA) as a tool to study the role of p38 MAPKs as regulators of keratinocyte differentiation. We demonstrate that OA activates p38delta but not other p38 isoforms. p38delta activation is increased as early as 0.5 h after OA addition, and activity is maximal at 8 and 24 h. ERK1 and ERK2 activity are reduced on an identical time course. We show that p38delta forms a complex with ERK1/2, and overexpression of p38delta inhibits ERK1/2 activity without reducing ERK1/2 level. Thus, p38delta may directly suppress ERK1/2 activity. Additional studies show that p38delta is expressed in the epidermis, suggesting a role for p38delta in regulating differentiation. To evaluate its function, we show that increased p38delta activity is associated with increased levels of AP1 and CAATT enhancer binding protein factors, increased binding of these factors to the involucrin (hINV) promoter, and increased expression. Moreover, these responses are maintained in the presence of SB203580, an agent that inhibits p38alpha and beta, further suggesting a central role for the p38delta isoform. Dominant-negative p38 also inhibits these responses. These unique observations suggest that p38delta is the major p38 isoform driving suprabasal hINV gene expression and that p38delta directly regulates ERK1/2 activity via formation of a p38delta-ERK1/2 complex.