Calcium activation of ERK mediated by calmodulin kinase I

John M. Schmitt, Gary A. Wayman, Naohito Nozaki, Thomas Soderling

    Research output: Contribution to journalArticle

    108 Citations (Scopus)

    Abstract

    Elevated intracellular Ca2+ triggers numerous signaling pathways including protein kinases such as the calmodulin-dependent kinases (CaMKs) and the extracellular signal-regulated kinases (ERKs). In the present study we examined Ca2+-dependent "cross-talk" between these two protein kinase families. Using a combination of pharmacological inhibitors and dominant-negative kinases (dnKinase), we identified a requirement for CaMKK acting through CaMKI in the stimulation of ERKs upon depolarization of the neuroblastoma cell line, NG108. Depolarization stimulated prolonged ERK and JNK activation that was blocked by the CaMKK inhibitor, STO-609; this inhibition of ERK activation by STO-609 was rescued by expression of a STO-609-insensitive mutant of CaMKK. However, activation of ERK by epidermal growth factor or carbachol were not suppressed by inhibition of CaMKK, indicating specificity for this "cross-talk." To identify the downstream target of CaMKK that mediated ERK activation upon depolarization, dnKinases were expressed. The dnCaMKI completely suppressed ERK2 activation whereas dnAKT/PKB or nuclear-targeted dnCaMKIV, other substrates for CaMKK, were not inhibitory. ERK activation upon depolarization or transfection with constitutively active (ca) CaMKI was blocked by dnRas. Additionally, depolarization of NG108 cells promoted neurite outgrowth, and this effect was blocked by inhibition of either CaMKK (STO-609) or ERK (UO126). Co-transfection with caCaMKK plus caCaMKI also stimulated neurite outgrowth that was blocked by inhibition of ERK (UO126). These data are the first to suggest that ERK activation and neurite outgrowth in response to depolarization are mediated by CaMKK activation of CaMKI.

    Original languageEnglish (US)
    Pages (from-to)24064-24072
    Number of pages9
    JournalJournal of Biological Chemistry
    Volume279
    Issue number23
    DOIs
    StatePublished - Jun 4 2004

    Fingerprint

    Calcium-Calmodulin-Dependent Protein Kinase Kinase
    Calcium-Calmodulin-Dependent Protein Kinases
    Extracellular Signal-Regulated MAP Kinases
    Chemical activation
    Calcium
    Depolarization
    Protein Kinases
    Transfection
    Carbachol
    Calmodulin
    Neuroblastoma
    Epidermal Growth Factor
    Phosphotransferases
    Cells
    Pharmacology

    ASJC Scopus subject areas

    • Biochemistry

    Cite this

    Schmitt, J. M., Wayman, G. A., Nozaki, N., & Soderling, T. (2004). Calcium activation of ERK mediated by calmodulin kinase I. Journal of Biological Chemistry, 279(23), 24064-24072. https://doi.org/10.1074/jbc.M401501200

    Calcium activation of ERK mediated by calmodulin kinase I. / Schmitt, John M.; Wayman, Gary A.; Nozaki, Naohito; Soderling, Thomas.

    In: Journal of Biological Chemistry, Vol. 279, No. 23, 04.06.2004, p. 24064-24072.

    Research output: Contribution to journalArticle

    Schmitt, JM, Wayman, GA, Nozaki, N & Soderling, T 2004, 'Calcium activation of ERK mediated by calmodulin kinase I', Journal of Biological Chemistry, vol. 279, no. 23, pp. 24064-24072. https://doi.org/10.1074/jbc.M401501200
    Schmitt, John M. ; Wayman, Gary A. ; Nozaki, Naohito ; Soderling, Thomas. / Calcium activation of ERK mediated by calmodulin kinase I. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 23. pp. 24064-24072.
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