Apoptosis signal-regulating kinase 1 (ASK1) is an intracellular inducer ofkeratinocyte differentiation

Cells differentiate in response to various extracellular stimuli. This cell ular response requires intracellular signaling pathways. The mitogen-activa ted protein (MAP) kinase cascade is a core signal transduction pathway that determines the fate of many kinds of cell. MAP kinase kinase kinase activa tes MAP kinase kinase, which in turn activates MAP kinase. Apoptosis signal -regulating kinase (ASK1) was Identified as a MAP kinase kinase kinase invo lved in the stress-induced apoptosis-signaling cascade that activates the S EK1-JNK and MKK3/MKK6-p38 MAP kinase cascades. Expression of the constituti vely active form of ASK1 (ASK1-DeltaN) in keratinocytes induced significant morphological changes and differentiation markers, transglutaminase-1, lor icrin, and involucrin, A transient increase in p21(Cip1/WAF1) reduced DNA s ynthesis, and cell cycle analysis verified the differentiation. p38 MAP kin ase inhibitors, SB202190 and SB203580, abolished the induction of different iation markers, transglutaminase-l, loricrin, and involucrin. In turn, the induction of differentiation with ceramide in keratinocytes caused an incre ase in ASK1 expression and activity. Furthermore, normal human skin express es ASK1 protein in the upper epidermis, implicating ASK1 in in vivo keratin ocyte differentiation. We propose that the ASK1-p38 MAP kinase cascade is a new intracellular regulator of keratinocyte differentiation.