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. E xtracellular signal-regulated kinase 3 (ERK3) (mitogen-activated protein kinase 6 [MAPK6]) and ERK4 (MAPK4) belong to the group of atypical MAPKs which display a SEG motif in the activation loop (instead of TEY) and carry a long C-terminal extension (1, 15, 58). The regulation, substrate specificity, and physiological functions of atypical MAP kinases are not completely understood (7). The phosphorylation of ERK3 and ERK4 at the serine residue in their activation loop proceeds through upstream protein kinase(s), such as the recently identified p21-activated protein kinases (PAKs) (8, 10), and leads to their activation (6, 9, 37). ERK3 also interacts with the protein phosphatase Cdc14A and is probably an in vivo substrate for this enzyme (16). The recent targeted deletion of ERK3 in mouse indicates that this enzyme is essential for neonatal survival and critical for the establishment of fetal growth potential and pulmonary function. The surviving ERK3-deficient pups show reduced reflexes and diminished ability to suckle (25). In contrast, the targeted inactivation of ERK4 in mice does not compromise the embryonic development, viability, and fertility of these animals and does not exacerbate the ERK3 phenotype, but it leads to a depression-related behavior in a forced swimming test (38).Only one substrate has been described for ERK3 and ERK4 so far, namely, the MAPK-activated protein (MAPKAP) kinase MK5 (also known as PRAK) (1,19,41,42). MK5 binds to ERK3 and ERK4 via a novel MAPK interaction motif (2). An increased level of cytoplasmic ERK3 causes the nuclear-cytoplasmic translocation of MK5, the formation of ERK3/MK5 signaling complexes, and the subsequent activation of MK5 by phosphorylation. The findings that the small interfering RNA (siRNA)-mediated knockdown of ERK3 reduces intracellular MK5 activity (1) and that the ERK3 level is reduced in MK5-deficient cells (41) clearly demonstrate the functional exis...

Recruitment of septin cytoskeletal proteins by Botulinum toxin A protease determines its remarkable stability

“…It is also possible that septins attenuate degradation of LCA owing to their interaction with other proteins. Septins are known to form scaffolds for protein recruitment and regulate multiple signaling events (Amin et al, 2008;Baust et al, 2008;Brand et al, 2012;Sharma et al, 2013;Xue et al, 2004). The specific signaling pathways involved in stabilization of LCA by septins remain to be identified.…”

The Catalytic Activity of the Mitogen-Activated Protein Kinase Extracellular Signal-Regulated Kinase 3 Is Required To Sustain CD4+ CD8+ Thymocyte Survival

“…In mice, ERK3 deficiency is associated with a defect in type II pneumocyte differentiation, leading to early neonatal death (15). Recent work has also uncovered a role for ERK3 in neuronal morphogenesis (16).…”

Structure and function of MK5/PRAK: the loner among the mitogen-activated protein kinase-activated protein kinases

“…Only a few MK5 substrates seem to be common with other MAPKAPKs. HSP27 and eEF2 kinase can also be phosphorylated by MK2 and MK3 (eEF2 kinase also by RSK), while Borg 2 and 3 are mutual substrates for MK2 and MK5 (Wang et al , 2001 ;Knebel et al , 2002 ;Brand et al , 2012 ). Human tyrosine hydroxylase can also be phosphorylated by MK2 in vitro , but while MK5 phosphorylates tyrosine hydroxylase at Ser-19, MK2 can additionally phosphorylate Ser-40 (Toska et al , 2002 ).…”

“…A mouse model for Angelman syndrome displays abnormalities in synaptic development and/or plasticity (Dindot et al , 2008 ). The ERK3/MK5 pathway has been shown to play a role in neural morphogenesis through the regulation of neuronal cytoskeleton and dendritic-spine formation (Brand et al , 2012 ). Thus, the E6AP and ERK3-MK5 network may collectively be involved in regulating neurological processes.…”