Abstract
In the present study we examined the possible role of p90Rsk in pathways leading to neuronal differentiation of PC12 cells induced by nerve growth factor (NGF) and the calcium ionophore ionomycin. PC12-M17 cells, expressing a dominant inhibitory Ras protein, do not undergo neuronal differentiation in response to NGF like wild-type PC12 cells, but exhibit neurite outgrowth when treated with NGF in combination with ionomycin. However, the blockade of Ras in these cells results in failure of activation of mitogen-activated protein kinase (MAPK)/extracellular signal regulation kinase (ERK) (MEK) and ERK activation as well, therefore kinases other than those of the ERK pathway might play a role in the induction of neuronal differentiation in this case. Here we show that p90Rsk translocates to the nucleus in response to ionomycin in both wild-type PC12 and PC12-M17 cells, and this spatial distribution is followed by increased phosphorylation of the cAMP response element binding protein (CREB). Since CREB is believed to be the transcription factor that can integrate Ca2+, growth factor and cAMP-induced signals, we suggest that p90Rsk may be one of the kinases which is able to replace ERKs under certain circumstances, thereby participating in Ras-independent neuronal differentiation induced by NGF plus ionomycin.
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Blenis, J., Kuo, C. J., Erikson, R. L. (1987) Identification of a ribosomal protein S6 kinase regulated by transformation and growth promotion stimuli. J. Biol. Chem. 262, 14373–14376.
Blenis, J. (1993) Signal transduction via the MAP kinases: proceed at your own Rsk. Proc. Natl. Acad. Sci. USA 90, 5889–5892.
Bhatt, R. R., Ferrell, J. E. Jr. (2000) Cloning and characterization of Xenopus Rsk2, the predominant Rsk isozyme in oocytes and eggs. J. Biol. Chem. 275, 32983–32990.
Bonni, A., Brunet, A., West, A. E., Datta, S. R., Takasu M. A., Greenberg, M. E. (1999) Cell survival promoted by the Ras-MAPK signaling pathways via transcription-dependent and -independent mechanisms. Science 286, 1358–1362.
Bruning, J. C., Gillette J. A., Zhao, Y., Bjorbaeck, C., Kotzka, J., Knebel, B., Hanstein, B., Lingohr, P., Moller, D. E., Krone, W., Kahn, C. R., Muller-Wiel, B. (2000) Ribosomal subunit kinase-2 is required for growth factor-stimulated transcription of the c-Fos gene. Proc. Natl. Acad. Sci. USA 97, 2462–2467.
Chen, R. H., Blenis, J. (1990) Identification of Xenopus S6 protein kinase homologs in somatic cells: phosphorylation and activation during initiation of cell proliferation. Mol. Cell. Biol. 10, 3204–3215.
Chen, R. H., Chung, J., Blenis, J. (1991) Regulation of p90Rsk phosphorylation and S6 phospho-transferase activity in Swiss 3T3 cells by growth factor-, phorbol ester-, and cyclic AMP-mediated signal transduction. Mol. Cell. Biol. 11, 1861–1867.
Chen, R. H., Sarnecki, Ch., Blenis, J. (1992) Nuclear localization and regulation of erk- and rsk-encoded protein kinases. Mol. Cell. Biol. 12, 915–923.
Corbit, K. C., Foster, D. A., Rich Rosner, M. (1999) Protein kinase Cd mediates neurogenic but not mitogenic activation of mitogen-activated protein kinase in neuronal cells. Mol. Cell. Biol. 19, 4209–4218.
Douville, E., Downward, J. (1997) EGF induced Sos phosphorylation in PC12 cells involves p90Rsk2. Oncogene 15, 373–383.
Erikson, E., Maller, J. L. (1986) Purification and characterization of a protein kinase from Xenopus eggs highly specific for ribosomal protein S6. J. Biol. Chem. 261, 350–355.
Frodin, M., Gammeltoft, S. (1999) Role and regulation of 90 kDa ribosomal S6 kinase in transduction. Mol. Cell. Endocrinol. 151, 65–77.
Gotoh, I., Nishida, E., Yamashita, T., Hoshi, M., Kawakami, M., Sakai, H. (1990) Microtubule-asso-ciated protein kinase activated by nerve growth factor and epidermal growth factor in PC12 cells. Eur. J. Biochem. 193, 661–669.
Greene, L. A., Tischler, A. S. (1976) Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc. Natl. Acad. Sci. USA 73, 2424–2428.
Gross, S. D., Schwab, M. S., Taieb, F. E., Lewellyn, A. L., Qian, Y. W., Maller, J. L. (2000) The critical role of the MAP kinase pathways in meiosis II in Xenopus oocytes is mediated by p90Rsk. Curr. Biol. 10, 430–438.
Hansen, T. v O., Rehfeld, J. F., Nielsen, F. C. (2000) Cyclic AMP-induced neuronal differentiation via activation of p38 mitogen-activated protein kinase. J. Neurochem. 75, 1870–1877.
Hsiao, K. M., Chou, S. Y., Shih, S. J., Ferrell, J. E. Jr. (1994) Evidence that inactive p42 MAP kinase and inactive Rsk exist as a heterodimer in vivo. Proc. Natl. Acad. Sci. USA 91, 5480–5484.
Impey, S., Obrietan, K., Wong, S. T., Poser, S., Yano, S., Wayman, G., Deloulme, J. C., Chan, G., Storm, D. R. (1998) Cross talk between ERK and PKA is required for Ca2+ stimulation of CREB-dependent transcription and ERK nuclear translocation. Neuron 21, 869–883.
Marshall, C. J. (1995) Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase action. Cell 80, 179–185.
Merienne, K., Jacquot, S., Zeniou, M., Pannetier, S., Sassone-Corsi, P., Hanauer, A. (2000) Action of Rsk by UV-light: phosphorylation dynamics and the involvement of the MAPK pathway. Oncogene 19, 4221–4229.
Miranti, C. K., Ginty, D. D., Huand, G., Chatila, T., Greenberg, M. E. (1995) Calcium activates serum response factor-dependent transcription by a Ras- and Elk-1-independent mechanism that involves a Ca2+/calmodulin-dependent kinase. Mol. Cell. Biol. 15, 3672–3684.
Moller, D. E., Xia, C. H., Tang, W., Zhu, A. X., Jakubowski, M. (1994) Human Rsk isoforms: cloning and characterization of tissue-specific expression. Am. J. Physiol. 266, 351–359.
Nguyen, T. T., Scimeca, J. C., Filloux, C., Peraldi, P., Carpentier, J. L., van Obberghen, E. (1993) Co-regulation of the mitogen-activated protein kinase, extracellular signal-regulated kinase 1, and the 90-kDa ribosomal S6 kinase in PC12 cells. J. Biol. Chem 268, 9803–9810.
Pap, M., Szeberényi, J. (1998) Differential Ras-dependence of gene induction by nerve growth factor and second messenger analogues in PC12 cells. Neurochem. Res. 23, 971–977.
Sassone-Corsi, P., Mizzen, C. A., Cheung, P., Crosio, C., Monaco, L., Jacquot, S., Hanauer, A., Allis, C. D. (1999) Requirement of Rsk2 for epidermal growth factor-activated phosphorylation of histone H3. Science 286, 886–891.
Shimamura, A., Ballif, B. A., Richards, S. A., Blenis, J. (2000) Rsk1 mediates a MEK-MAP kinase cell survival signal. Curr. Biol. 10, 127–135.
Szeberényi, J., Cai, H., Cooper, G. M. (1990) Effect of a dominant inhibitory Ha-ras mutation on neuronal differentiation of PC12 cells. Mol. Cell. Biol 10, 5324–5332.
Szeberényi, J., Erhardt, P., Cai, H., Cooper, G. M. (1992) Role of Ras in signal transduction from the NGF receptor: relationship to protein kinase C, calcium and cyclic AMP. Oncogene 7, 2105–2113.
Szeberényi, J., Erhardt, P. (1994) Cellular components of nerve growth factor signaling. Biochim. Biophys. Acta 1222, 187–202.
Takahashi, E., Abe, J., Berk, B. C. (1997) Angiotensin II stimulates p90Rsk in vascular smooth muscle cells. A potential Na+-H+ exchanger kinase. Circ. Res. 81, 268–273.
Traverse, S., Gomez, N., Paterson, H., Marshall, C. J., Cohen, P. (1992) Sustained activation of the mitogen-activated protein (MAP) kinase cascade may be required for differentiation of PC12 cells. Biochem. J. 288, 351–355.
Wong, E. V., Schaefer, A. W., Landreth, G., Lemmon, V. (1996) Involvement of p90Rsk in neurite outgrowth mediated by the adhesion molecule L1. J. Biol. Chem. 271, 18217–18223.
Wood, K. W., Sarnecki, Ch., Roberts, T. M., Blenis, J. (1992) ras mediates nerve growth factor receptor modulation of three signal-transducing protein kinases: MAP kinase, Raf-1 and RSK. Cell 68, 1041–1050.
Xing, J., Kornhauser, J. M., Xia, Z., Thiele, E. A., Greenberg, M. E. (1998) Nerve growth factor activates extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways to stimulate CREB serine 133 phosphorylation. Mol. Cell. Biol. 18, 1945–1955.
Xing, J., Ginty, D. D., Greenberg, M. E. (1996) Coupling of the Ras-MAPK pathway to gene activation by Rsk2, a growth factor-regulated CREB kinase. Science 273, 959–963.
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Boglári, G., Szeberényi, J. Nuclear Translocation of p90Rsk and Phosphorylation of CREB is Induced by Ionomycin in a Ras-Independent Manner in PC12 Cells. BIOLOGIA FUTURA 53, 325–334 (2002). https://doi.org/10.1556/ABiol.53.2002.3.9
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DOI: https://doi.org/10.1556/ABiol.53.2002.3.9