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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Base Sequence
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DNA Primers / genetics
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Dendrites / metabolism*
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Dendrites / ultrastructure*
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GTP-Binding Protein Regulators / metabolism
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Guanine Nucleotide Exchange Factors / metabolism
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HEK293 Cells
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HeLa Cells
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Hippocampus / cytology
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Hippocampus / metabolism
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Humans
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Intracellular Signaling Peptides and Proteins / chemistry
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Intracellular Signaling Peptides and Proteins / deficiency
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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MAP Kinase Signaling System
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Mice
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Mice, Knockout
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Mitogen-Activated Protein Kinase 6 / chemistry
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Mitogen-Activated Protein Kinase 6 / genetics
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Mitogen-Activated Protein Kinase 6 / metabolism*
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Models, Neurological
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Multiprotein Complexes / chemistry
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Multiprotein Complexes / metabolism
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Neurogenesis / physiology
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Neurons / metabolism
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Neurons / ultrastructure
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Protein Serine-Threonine Kinases / chemistry
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Protein Serine-Threonine Kinases / deficiency
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Septins / chemistry
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Septins / genetics
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Septins / metabolism*
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Transfection
Substances
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DNA Primers
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GTP-Binding Protein Regulators
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Guanine Nucleotide Exchange Factors
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Intracellular Signaling Peptides and Proteins
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KALRN protein, mouse
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Multiprotein Complexes
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Recombinant Fusion Proteins
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MAP-kinase-activated kinase 5
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Protein Serine-Threonine Kinases
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Mapk6 protein, mouse
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Mitogen-Activated Protein Kinase 6
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Sept7 protein, mouse
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Septins