Abstract
ABSTRACTThe actin motor protein non-muscle myosin II (NMII) acts as a master regulator of cell morphology, with a role in several essential cellular processes, including cell migration and post-synaptic dendritic spine plasticity in neurons. NMII also generates forces that alter biochemical signaling, by driving changes in interactions between actin-associated proteins that can ultimately regulate gene transcription. In addition to its roles in normal cellular physiology, NMII has recently emerged as a critical regulator of diverse, genetically complex diseases, including neuronal disorders, cancers and vascular disease. In the context of these disorders, NMII regulatory pathways can be directly mutated or indirectly altered by disease-causing mutations. NMII regulatory pathway genes are also increasingly found in disease-associated copy-number variants, particularly in neuronal disorders such as autism and schizophrenia. Furthermore, manipulation of NMII-mediated contractility regulates stem cell pluripotency and differentiation, thus highlighting the key role of NMII-based pharmaceuticals in the clinical success of stem cell therapies. In this Review, we discuss the emerging role of NMII activity and its regulation by kinases and microRNAs in the pathogenesis and prognosis of a diverse range of diseases, including neuronal disorders, cancer and vascular disease. We also address promising clinical applications and limitations of NMII-based inhibitors in the treatment of these diseases and the development of stem-cell-based therapies.
Highlights
Non-muscle myosin II (NMII) is a major contributor to cellular organization, polarity and regulation, with altered non-muscle myosin II (NMII) activity contributing to numerous disease pathologies
(Chen et al, 2010, 2014; Kim et al, 2015; Walker et al, 2010). This Review focuses on how NMII and its regulatory pathways contribute to various disorders, while exploring potential therapeutic benefits and limitations of NMII inhibitors in disease treatment and stem cell therapies
In support of this hypothesis, the knockdown of the non-syndromic mental retardation (MR)-related protein oligophrenin in rat hippocampal slices resulted in decreased spine density and/or length, which could be rescued by inhibition of myosin activity (Govek et al, 2004; Nadif Kasri et al, 2009)
Summary
Non-muscle myosin II (NMII) is a major contributor to cellular organization, polarity and regulation, with altered NMII activity contributing to numerous disease pathologies. We discuss evidence for an emerging role of microRNAs (miRNAs; see Box 1) in the regulation of NMII activity in disease Because both differential NMII expression and regulation can impact disease pathology, the following section discusses the structure of NMII, different NMII isoforms, and how phosphorylation mediates its association with and bundling of actin filaments, resulting in morphological and signaling changes. Box 1), which manifest with altered post-synaptic spine morphology and/or density (reviewed in Penzes et al, 2011) These disorders include: neurodevelopmental disorders, such as autism; neurodegenerative disorders, such as Alzheimer’s disease; neuronal migration disorders, such as lissencephaly (Tsai et al., In neurons, NMII localizes to dynamic actin-enriched structures, including growth cones (see Box 1) and synapses (Fig. 2). NMII serves as an important regulator of stimuli-induced changes in spine morphology that underlie learning and memory formation (reviewed in Hotulainen and Hoogenraad, 2010)
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