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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    • "In particular, myosin motor proteins, which bind to and travel along actin filaments, control multiple processes in microvilli and stereocilia. Myosins have been implicated in transporting, anchoring and concentrating protein complexes and membrane vesicles, in exerting tension force on the plasma membrane and in influencing the structure of actin networks (reviewed by Krendel and Mooseker, 2005; Nambiar et al., 2010; Schwander et al., 2010; Hartman et al., 2011). One of the myosins that regulates actin-rich membrane protrusions in Drosophila and vertebrates is Myosin VIIA (Myo7A) (reviewed by El-Amraoui et al., 2008). "
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    ABSTRACT: Microvilli and related actin-based protrusions permit multiple interactions between cells and their environment. How shape, length, and arrangement of microvilli are determined remains largely unclear. To address this issue and explore the cooperation of the two main components of a microvillus, the central F-actin bundle and the enveloping plasma membrane, we investigated expression and function of Myosin VIIA (Myo7A), which is encoded by crinkled (ck), and its interaction with cadherin Cad99C in the microvilli of the Drosophila follicular epithelium. Myo7A is present in the microvilli and terminal web of follicle cells, and associates with several other F-actin-rich structures in the ovary. Loss of Myo7A caused brush border defects and a reduction in the amount of the microvillus regulator Cad99C. We show that Myo7A and Cad99C form a molecular complex and that the cytoplasmic tail of Cad99C recruits Myo7A to microvilli. Our data indicate that Myo7A regulates the structure and spacing of microvilli, and interacts with Cad99C in vivo. A comparison of the mutant phenotypes suggests that Myo7A and Cad99C have co-dependent and independent functions in microvilli.
    Development 09/2014; 127(22). DOI:10.1242/jcs.099242 · 6.46 Impact Factor
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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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