Functional characterization of the ERK3 / MK5 / septin-7 ternary complex: neuronal morphogenesis and beyond

Manoj Balakrishna Menon ¹ Frank Brand ¹ Stefanie Schumacher ¹ Shashi Kant ^1,2 Ruth Simon ³ Benjamin Turgeon ⁴ Stefan Britsch ³ Sylvain Meloche ⁴ Alexey Kotlyarov ¹ Matthias Gaestel ¹

¹Institute of Physiological Chemistry, Medical School Hannover, Hannover
²Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts
³Institute of Molecular and Cellular Anatomy, University of Ulm, Ulm
⁴Institut de Recherche en Immunologie et Cancérologie, Université de Montréal, Montreal

The physiological functions and the downstream targets of the atypical MAP kinase-ERK3-MAPKAP kinase-5 signaling complex are rather enigmatic so far (1). Recently, we have identified septin-7 (Sept7) as a novel interaction partner of the atypical MAP kinase ERK3 in a large scale interaction screen. Septins are cytoskeletal GTP-binding proteins with evolutionatily conserved roles in cytokinesis. Mammalian septins are involved in diverse processes, such as the control of cell polarity and secretion, cortical organization, and cell cycle regulation, ciliogenesis as well as dendritic spine formation (2). Co-expression of Sept7 recruits ERK3 to filamentous cytoplasmic structures. ERK3/MK5/Sept7 form a ternary complex, which can phosphorylate the Sept7 regulators designated Binders of Rho GTPases (Borgs). In transfected primary neurons, Sept7-dependent dendrite development and spine formation are stimulated by the ERK3/MK5 module. Consistent with a role for ERK3/MK5 signaling in neuronal morphogenesis, MK5-deficient mice displayed impaired dendritic spine formation in hippocampal neurons in vivo. Thus, the regulation of neuronal morphogenesis is proposed as the first physiological function of the ERK3/MK5/Sept7 signaling module (3). Obligatory deletion of the Sept7 gene causes embryonic lethality in mice (4). To further characterize the in vivo function of the ERK3/Sept7 signaling module, we generated the conditional Sept7 knockout mouse. Deletion of Sept7 in fibroblasts leads to severe growth retardation, defective cytokinesis and multinucleation. Interestingly, ERK3- and MK5-deficient mouse embryonic fibroblasts also display a significantly enhanced number of multinucleated cells. Further studies are necessary to decipher the role played by the ERK3/MK5/Sept7 complex in mammalian cyokinesis.

REFERENCES:

1. S. Schumacher et al., EMBO J 23, 4770 (Dec 8, 2004).

2. S. Mostowy, P. Cossart, Nat Rev Mol Cell Biol 13, 183 (Mar, 2012).

3. F. Brand et al., Molecular and Cellular Biology 32, 2467 (2012).

4. M. Kinoshita, in The Septins. (John Wiley & Sons, Ltd, 2008), pp. 319-336.