Calcium activation of ERK mediated by calmodulin kinase I

John M Schmitt; Gary A Wayman; Naohito Nozaki; Thomas R Soderling

doi:10.1074/jbc.M401501200

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Calcium activation of ERK mediated by calmodulin kinase I

Journal article

Open access

Peer reviewed

Calcium activation of ERK mediated by calmodulin kinase I

John M Schmitt, Gary A Wayman, Naohito Nozaki and Thomas R Soderling

The Journal of biological chemistry, Vol.279(23), pp.24064-24072

06/04/2004

DOI: https://doi.org/10.1074/jbc.M401501200

Handle:

https://hdl.handle.net/2376/108146

PMID: 15150258

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Abstract

Immunohistochemistry

Calcium - metabolism

Dose-Response Relationship, Drug

Mitogen-Activated Protein Kinase Kinases - metabolism

MAP Kinase Kinase 4

Transfection

Time Factors

Cell Division

JNK Mitogen-Activated Protein Kinases

Neurons - metabolism

Protein-Serine-Threonine Kinases - metabolism

Calcium-Calmodulin-Dependent Protein Kinases - physiology

Signal Transduction

Cells, Cultured

Rats

Plasmids - metabolism

Blotting, Western

Precipitin Tests

Calcium-Calmodulin-Dependent Protein Kinase Kinase

Animals

Cell Line, Tumor

Mice

Enzyme Activation

Calcium-Calmodulin-Dependent Protein Kinases - metabolism

Microscopy, Fluorescence

Mitogen-Activated Protein Kinases - metabolism

Elevated intracellular Ca(2+) 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 Ca(2+)-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.

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Title: Calcium activation of ERK mediated by calmodulin kinase I
Creators: John M Schmitt - Vollum Institute, Oregon Health and Sciences University, Portland 97239, USA
Gary A Wayman
Naohito Nozaki
Thomas R Soderling
Publication Details: The Journal of biological chemistry, Vol.279(23), pp.24064-24072
Academic Unit: Integrative Physiology and Neuroscience, Department of
Publisher: United States
Grant note: T32 DK007680 / NIDDK NIH HHS DK007680 / NIDDK NIH HHS R01 GM 41292 / NIGMS NIH HHS R01 DK44239 / NIDDK NIH HHS
Identifiers: 99900547583601842
Language: English
Resource Type: Journal article