Principles of Unconventional Myosin Function and Targeting

Department of Biochemistry, Stanford University, Stanford, California 94305, USA.
Annual Review of Cell and Developmental Biology (Impact Factor: 16.66). 05/2011; 27(1):133-55. DOI: 10.1146/annurev-cellbio-100809-151502
Source: PubMed


Unconventional myosins are a superfamily of actin-based motors implicated in diverse cellular processes. In recent years, much progress has been made in describing their biophysical properties, and headway has been made into analyzing their cellular functions. Here, we focus on the principles that guide in vivo motor function and targeting to specific cellular locations. Rather than describe each motor comprehensively, we outline the major themes that emerge from research across the superfamily and use specific examples to illustrate each. In presenting the data in this format, we seek to identify open questions in each field as well as to point out commonalities between them. To advance our understanding of myosins' roles in vivo, clearly we must identify their cellular cargoes and the protein complexes that regulate motor attachment to fully appreciate their functions on the cellular and developmental levels.

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    • "The MLC is an essential component of this family that is responsible for cytoskeletal dynamics for communication, migration and cell division (Sellers, 2000; Redowicz, 2007; Hartman et al., 2011) Myosin has an important role in the processes related to structural stabilization and cellular dynamics, rendering the cell membrane resistant to potential deformations. Furthermore, myosin is involved in actin-enabled motor mechanisms and the organization of actin in the intracellular space (Hartman et al., 2011; Kneussel and Wagner, 2013). FLNa, a substrate of PAK, is also an important cellular structural component. "
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    ABSTRACT: PAKs are a family of serine/threonine protein kinases activated by small GTPases of the Rho family, including Rac and Cdc42, and are categorized into group I (isoforms 1, 2 and 3) and group II (isoforms 4, 5 and 6). PAK1 and PAK3 are critically involved in biological mechanisms associated with neurodevelopment, neuroplasticity and maturation of the nervous system, and changes in their activity have been detected in pathological disorders, such as Alzheimer's disease, Huntington's disease and mental retardation. The group I PAKs have been associated with neurological processes due to their involvement in intracellular mechanisms that result in molecular and cellular morphological alterations that promote cytoskeletal outgrowth, increasing the efficiency of synaptic transmission. Their substrates in these processes include other intracellular signaling molecules, such as Raf, Mek and LIMK, as well as other components of the cytoskeleton, such as MLC and FLNa. In this review, we describe the characteristics of group I PAKs, such as their molecular structure, mechanisms of activation and importance in the neurobiological processes involved in synaptic plasticity.
    Journal of Physiology-Paris 08/2014; 108(4-6). DOI:10.1016/j.jphysparis.2014.08.007 · 1.90 Impact Factor
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    • "Myosins are a large superfamily of actin-based molecular motors involved in a wide variety of cellular functions that include organellar and molecular transport, mitosis and cytokinesis, motility, signal transduction, and maintenance of cell shape [1], [2], [3]. Myosin heavy chains are composed of a head domain that binds actin in an ATP-dependent manner, a neck domain with one or more light chain binding sites (IQ motifs), and a variety of specialized tail domains. "
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    ABSTRACT: Osteoclasts are large, multinucleated cells of the monocyte-macrophage lineage that generate specialized substrate adhesion complexes to facilitate their function as bone-degrading cells. The patterning and function of these actin-based complexes, podosomes and sealing zones, are regulated by the small GTPase Rho. Myosin IXB (Myo9b) is a unique actin-based motor protein that contains a RhoGAP domain, which, like other RhoGAPs, is inhibitory to Rho signaling. In this study, Myo9b is shown to be expressed in osteoclasts and act as a critical regulator of podosome patterning and osteoclast function. SiRNA-mediated knockdown of Myo9b results in increased activity of Rho but not Rac in osteoclasts. Knockdown in osteoclasts on glass results in altered podosome patterning and decreased motility, and this effect is reversed by addition of a Rho inhibitor. SiRNA-mediated suppression of Myo9b expression in osteoclasts on bone results in a dramatic loss of resorptive capacity even though sealing zones appear normal. This loss of resorption is also reversible with addition of a Rho inhibitor. Cells with diminished Myo9b levels display mislocalization and suppressed activation of Src, a tyrosine kinase with critical effects on osteoclast actin cytoskeletal rearrangement and function. In addition, siRNA-treated cells display poorly formed microtubule networks and a lack of tubulin acetylation, a marker of microtubule stability. However, short-term addition of TNFα to cells with suppressed Myo9b levels overcomes or circumvents these defects and causes increased sealing zone size and resorptive capacity. These results indicate that the RhoGAP activity of Myo9b plays a key role in regulating the actin-based structures necessary for osteoclast motility and resorption, and confirms that Myo9b can act as a motorized signaling molecule that links Rho signaling to the dynamic actin cytoskeleton.
    PLoS ONE 01/2014; 9(1):e87402. DOI:10.1371/journal.pone.0087402 · 3.23 Impact Factor
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    • "The first two act as motors on microtubule filaments, while myosins function on actin (Vale 2003). Myosins participate in a variety of cellular processes, including cytokinesis , organellar transport, cell polarization, transcriptional regulation, intracellular transport, and signal transduction (Hofmann et al. 2009; Bloemink and Geeves 2011; Hartman et al. 2011). They bind to filamentous actin and produce physical forces by hydrolyzing ATP and converting chemical energy into mechanical force (Hartman and Spudich 2012). "
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    ABSTRACT: Myosins are key components of the eukaryotic cytoskeleton, providing motility for a broad diversity of cargoes. Therefore, understanding the origin and evolutionary history of myosin classes is crucial to address the evolution of eukaryote cell biology. Here, we revise the classification of myosins using an updated taxon sampling that includes newly or recently sequenced genomes and transcriptomes from key taxa. We performed a survey of eukaryotic genomes and phylogenetic analyses of the myosin gene family, reconstructing the myosin toolkit at different key nodes in the eukaryotic tree of life. We also identified the phylogenetic distribution of myosin diversity in terms of number of genes, associated protein domains and number of classes in each taxa. Our analyses show that new classes (i.e. paralogs) and domain architectures were continuously generated throughout eukaryote evolution, with a significant expansion of myosin abundance and domain architectural diversity at the stem of Holozoa, predating the origin of animal multicellularity. Indeed, single-celled holozoans have the most complex myosin complement among eukaryotes, with paralogs of most myosins previously considered animal-specific. We recover a dynamic evolutionary history, with several lineage-specific expansions (e.g. the 'myosin III-like' gene family diversification in choanoflagellates), convergence in protein domain architectures (e.g. fungal and animal chitin synthase myosins), and important secondary losses. Overall, our evolutionary scheme demonstrates that the ancestral eukaryote likely had a complex myosin repertoire that included six genes with different protein domain architectures. Finally, we provide an integrative and robust classification, useful for future genomic and functional studies on this crucial eukaryotic gene family.
    Genome Biology and Evolution 01/2014; DOI:10.1093/gbe/evu013 · 4.23 Impact Factor
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