MITOGEN-ACTIVATED AND STRESS-ACTIVATED PROTEIN KINASE-1 (MSK1) IS DIRECTLY ACTIVATED BY MAPK AND SAPK2 P38, AND MAY MEDIATE ACTIVATION OF CREB/

We have identified a novel mitogen- and stress-activated protein kinas e (MSK1) that contains two protein kinase domains in a single polypept ide, MSK1 is activated in vitro by MAPK2/ERK2 or SAPK2/p38, Endogenous MSK1 is activated in 293 cells by either growth factor/phorbol ester stimulation, or by exposure to UV radiation, and oxidative and chemica l stress. The activation of MSK1 by growth factors/phorbol esters is p revented by PD 98059, which suppresses activation of the MAPK cascade, while the activation of MSK1 by stress stimuli is prevented by SB 203 580, a specific inhibitor of SAPK2/p38, In HeLa, PC12 and SK-N-MC cell s, PD 98059 and SE 203580 are both required to suppress the activation of MSK1 by TNF, NGF and FGF, respectively, because these agonists act ivate both the MAPK/ERK and SAPK2/p38 cascades. MSK1 is localized in t he nucleus of unstimulated or stimulated cells, and phosphorylates CRE B at Ser133 with a K-m value far lower than PKA, MAPKAP-K1 (p90Rsk) an d MAPKAP-K2, The effects of SE 203580, PD 98059 and Ro 318220 on agoni st-induced activation of CREB and ATF1 in four cell-lines mirror the e ffects of these inhibitors on MSK1 activation, and exclude a role for MAPKAP-K1 and MAPKAP-K2/3 in this process. These findings, together wi th other observations, suggest that MSK1 may mediate the growth-factor and stress-induced activation of CREB.