The Extracellular Signal-Regulated Kinase 3 (Mitogen-Activated Protein Kinase 6 [MAPK6])–MAPK-Activated Protein Kinase 5 Signaling Complex Regulates Septin Function and Dendrite Morphology

Abstract

Mitogen-activated protein kinase-activated protein (MAPKAP) kinase 5 (MK5) deficiency is associated with reduced extracellular signal-regulated kinase 3 (ERK3) (mitogen-activated protein kinase 6) levels, hence we utilized the MK5 knockout mouse model to analyze the physiological functions of the ERK3/MK5 signaling module. MK5-deficient mice displayed impaired dendritic spine formation in mouse hippocampal neurons in vivo. We performed large-scale interaction screens to understand the neuronal functions of the ERK3/MK5 pathway and identified septin7 (Sept7) as a novel interacting partner of ERK3. ERK3/MK5/Sept7 form a ternary complex, which can phosphorylate the Sept7 regulators Binders of Rho GTPases (Borgs). In addition, the brain-specific nucleotide exchange factor kalirin-7 (Kal7) was identified as an MK5 interaction partner and substrate protein. In transfected primary neurons, Sept7-dependent dendrite development and spine formation are stimulated by the ERK3/MK5 module. Thus, the regulation of neuronal morphogenesis is proposed as the first physiological function of the ERK3/MK5 signaling module.

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SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.06633-11.

ACKNOWLEDGMENTS

We thank Ami Aronheim (The Rappaport Institute, Israel), Ole-Morten Seternes (University of Tromso, Norway), Koh-ichi Nagata (Aichi Human Service Center, Japan), Betty Eipper (University of Connecticut), and Ian Macara (University of Virginia School of Medicine) for providing plasmid constructs and Ole-Morten Seternes (University of Tromso, Norway), Anne Hennig (Hannover Medical School), and ProQinase Gmbh (University of Freiburg) for recombinant proteins. We thank Evgeni Ponimaskin and Daria Guseva for technical support in setting up primary neuronal cultures, Rudolf Bauerfeind for technical support for the FRET measurements, and Juri Lafera (Hannover Medical School) for help with the cloning of recombinant plasmids.

This work was supported by Deutsche Forschungsgemeinschaft KO2091/1 (to A.K. and M.G.) and by a grant from the Canadian Institutes of Health Research (to S.M.).