title: 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.
authors.affiliation: Institute of Physiological Chemistry, Hannover Medical School, Hannover, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Brand
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schumacher
authors.forename: Shashi
authors.initials: S
authors.lastname: Kant
authors.forename: Manoj B
authors.initials: MB
authors.lastname: Menon
authors.forename: Ruth
authors.initials: R
authors.lastname: Simon
authors.forename: Benjamin
authors.initials: B
authors.lastname: Turgeon
authors.forename: Stefan
authors.initials: S
authors.lastname: Britsch
authors.forename: Sylvain
authors.initials: S
authors.lastname: Meloche
authors.forename: Matthias
authors.initials: M
authors.lastname: Gaestel
authors.forename: Alexey
authors.initials: A
authors.lastname: Kotlyarov
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D003712:Dendrites / Q000378:metabolism* / Q000648:ultrastructure*; D020555:GTP-Binding Protein Regulators / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D048053:Mitogen-Activated Protein Kinase 6 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008959:Models, Neurological; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D058112:Septins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D017931:DNA Primers; D020555:GTP-Binding Protein Regulators; D020662:Guanine Nucleotide Exchange Factors; D047908:Intracellular Signaling Peptides and Proteins; C548820:KALRN protein, mouse; D046912:Multiprotein Complexes; D011993:Recombinant Fusion Proteins; C111049:MAP-kinase-activated kinase 5; D017346:Protein Serine-Threonine Kinases; C474633:Mapk6 protein, mouse; D048053:Mitogen-Activated Protein Kinase 6; C512895:Sept7 protein, mouse; D058112:Septins