Cell cycle and cell survival: Pinpointing Rsks

Abstract

During development, some neurons undergo cell death if they are deprived of growth factors. Signals that contribute to such growth factor-dependent survival are mediated, at least in part, by activation of mitogen-activated protein kinases (MAPKs), but the crucial target of the MAPKs has been unknown. Bonni et al. report that the protein kinase Rsk2 (a member of the pp90 ribosomal protein S6 kinase family), which is phosphorylated and activated by MAPKs, may mediate the effects on cell survival in cerebellar granule neurons exposed to brain-derived neurotrophic factor. Rsk2 appears to have two ways of influencing cell survival: It phosphorylates and thus suppresses the effects of BAD, a protein that promotes apoptosis. Rsk2 also phosphorylates and activates the transcription factor CREB (cAMP response element binding protein). Activation of CREB may in turn enhance expression of Bcl2, a protein that promotes cell survival. Nebreda and Gavin discuss these findings and those from a pair of reports that define another role of Rsks in the control of the cell cycle. Before fertilization, most vertebrate eggs are at metaphase of meiosis II. Cytostatic factor (CSF) is the name given to an enzymatic activity present in such eggs, which, when injected into dividing embryos, causes mitotic arrest in metaphase. Such "CSF arrest" can be initiated by the protein kinase Mos, which activates the sequential activation of MAPK kinase MEK and the p42 MAPK. The critical target of p42 MAPK has now been identified as the protein kinase p90 Rsk. Bhatt and Ferrell show that depletion of Rsk from Xenopus egg extracts prevents mitotic arrest in response to activated Mos. Gross et al. demonstrate that activation of Rsk requires its phosphorylation by p42 MAPK and the 3-phosphatidylinositol-dependent kinase-1 (PDK-1). They also constructed a constitutively active form of Rsk that caused metaphase arrest when infected into blastomeres of two-cell Xenopus embryos. Activation of Rsk is thus necessary and sufficient to cause CSF arrest. Bonni, A., Brunet, A., West, A.E., Datta, S.R., Takasu, M.A., and Greenberg, M.A. (1999) Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 286 : 1358-1362. [Abstract] [Full Text] Bhatt, R.R. and Ferrell Jr., J.E. (1999) The protein Kinase p90 Rsk as an essential mediator of cytostatic factor activity. Science 286 : 1362-1365. [Abstract] [Full Text] Gross, S.D., Schwab, M.S., Lewellyn, A.L., and Maller, J.L. (1999) Induction of metaphase arrest in cleaving Xenopus embryos by the protein kinase p90Rsk. Science 286 : 1365-1367. [Abstract] [Full Text] Nebreda, A.R. and Gavin, A.-C. (1999) Cell survival demands some Rsk. Science 286 : 1309-1310. [Summary] [Full Text]