Kim JH, Cho A, Yin H et al.Psidin, a conserved protein that regulates protrusion dynamics and cell migration. Genes Dev 25:730-741

Department of Biological Chemistry, Center for Cell Dynamics, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA.
Genes & development (Impact Factor: 10.8). 03/2011; 25(7):730-41. DOI: 10.1101/gad.2028611
Source: PubMed


Dynamic assembly and disassembly of actin filaments is a major driving force for cell movements. Border cells in the Drosophila ovary provide a simple and genetically tractable model to study the mechanisms regulating cell migration. To identify new genes that regulate cell movement in vivo, we screened lethal mutations on chromosome 3R for defects in border cell migration and identified two alleles of the gene psidin (psid). In vitro, purified Psid protein bound F-actin and inhibited the interaction of tropomyosin with F-actin. In vivo, psid mutations exhibited genetic interactions with the genes encoding tropomyosin and cofilin. Border cells overexpressing Psid together with GFP-actin exhibited altered protrusion/retraction dynamics. Psid knockdown in cultured S2 cells reduced, and Psid overexpression enhanced, lamellipodial dynamics. Knockdown of the human homolog of Psid reduced the speed and directionality of migration in wounded MCF10A breast epithelial monolayers, whereas overexpression of the protein increased migration speed and altered protrusion dynamics in EGF-stimulated cells. These results indicate that Psid is an actin regulatory protein that plays a conserved role in protrusion dynamics and cell migration.

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Available from: Denise Montell, Jan 16, 2014
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    • "Psidin (known as NAA25 in mammals) is the auxiliary subunit of the NatB acetylation complex required for protein acetylation (Stephan et al., 2012). In addition, it has been shown that Psidin can act outside this complex as an ABP that regulates actin dynamics both in neurons and in non-neuronal cells of Drosophila (Kim et al., 2011; Stephan et al., 2012). These studies show that Psidin antagonises F-actin stabilisation mediated by Tropomyosin 1 in lamellipodia, which is required for the pathfinding of olfactory neurons in the fly brain. "
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    ABSTRACT: The extension of long slender axons is a key process of neuronal circuit formation, both during brain development and regeneration. For this, growth cones at the tips of axons are guided towards their correct target cells by signals. Growth cone behaviour downstream of these signals is implemented by their actin and microtubule cytoskeleton. In the first part of this Commentary, we discuss the fundamental roles of the cytoskeleton during axon growth. We present the various classes of actin- and microtubule-binding proteins that regulate the cytoskeleton, and highlight the important gaps in our understanding of how these proteins functionally integrate into the complex machinery that implements growth cone behaviour. Deciphering such machinery requires multidisciplinary approaches, including genetics and the use of simple model organisms. In the second part of this Commentary, we discuss how the application of combinatorial genetics in the versatile genetic model organism Drosophila melanogaster has started to contribute to the understanding of actin and microtubule regulation during axon growth. Using the example of dystonin-linked neuron degeneration, we explain how knowledge acquired by studying axonal growth in flies can also deliver new understanding in other aspects of neuron biology, such as axon maintenance in higher animals and humans.
    Journal of Cell Science 05/2013; 126(11). DOI:10.1242/jcs.126912 · 5.43 Impact Factor
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    • "Moreover, we found that invadopodia formation of A549 induced by EGF was inhibited by MMP inhibitor (GM6001). These results in lung cancer cells are consistant with the emerging evidences that suggest a critical role of EGF signaling pathway in the invadopodia formation as well as the invasiveness and metastasis of cancer cells [8], [9], [51], [54]. Since invadopodia are not vital for cell viability, it is suggested that anti-invadopodia therapy would be expected to have fewer side effects than current radio- and chemotherapy approaches in cancer therapeutics [11], [13]. "
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    ABSTRACT: Invadopodia or invasive feet, which are actin-rich membrane protrusions with matrix degradation activity formed by invasive cancer cells, are a key determinant in the malignant invasive progression of tumors and represent an important target for cancer therapies. In this work, we presented a microfluidic 3D culture device with continuous supplement of fresh media via a syringe pump. The device mimicked tumor microenvironment in vivo and could be used to assay invadopodia formation and to study the mechanism of human lung cancer invasion. With this device, we investigated the effects of epidermal growth factor (EGF) and matrix metalloproteinase (MMP) inhibitor, GM6001 on invadopodia formation by human non-small cell lung cancer cell line A549 in 3D matrix model. This device was composed of three units that were capable of achieving the assays on one control group and two experimental groups' cells, which were simultaneously pretreated with EGF or GM6001 in parallel. Immunofluorescence analysis of invadopodia formation and extracellular matrix degradation was conducted using confocal imaging system. We observed that EGF promoted invadopodia formation by A549 cells in 3D matrix and that GM6001 inhibited the process. These results demonstrated that epidermal growth factor receptor (EGFR) signaling played a significant role in invadopodia formation and related ECM degradation activity. Meanwhile, it was suggested that MMP inhibitor (GM6001) might be a powerful therapeutic agent targeting invadopodia formation in tumor invasion. This work clearly demonstrated that the microfluidic-based 3D culture device provided an applicable platform for elucidating the mechanism of cancer invasion and could be used in testing other anti-invasion agents.
    PLoS ONE 02/2013; 8(2):e56448. DOI:10.1371/journal.pone.0056448 · 3.23 Impact Factor
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    • "Birth of g9D À / À mice at lessthan-expected Mendelian frequency (Hook et al., 2011) suggests that these forms are required for efficient embryogenesis. Given the extensive migration events that occur during embryogenesis, potentially Tm5NM1/2 is required for specific migration events during embryogenesis, such as those reported in Drosophila embryos (Kim et al., 2011). Previous work has established that Rac is a major regulator of the rate of wound healing. "
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    ABSTRACT: Precise orchestration of actin polymer into filaments with distinct characteristics of stability, bundling, and branching underpins cell migration. A key regulator of actin filament specialization is the tropomyosin family of actin-associating proteins. This multi-isoform family of proteins assemble into polymers that lie in the major groove of polymerized actin filaments, which in turn determine the association of molecules that control actin filament organization. This suggests that tropomyosins may be important regulators of actin function during physiological processes dependent on cell migration, such as wound healing. We have therefore analyzed the requirement for tropomyosin isoform expression in a mouse model of cutaneous wound healing. We find that mice in which the 9D exon from the TPM3/γTm tropomyosin gene is deleted (γ9D -/-) exhibit a more rapid wound-healing response 7 days after wounding compared with wild-type mice. Accelerated wound healing was not associated with increased cell proliferation, matrix remodeling, or epidermal abnormalities, but with increased cell migration. Rac GTPase activity and paxillin phosphorylation are elevated in cells from γ9D -/- mice, suggesting the activation of paxillin/Rac signaling. Collectively, our data reveal that tropomyosin isoform expression has an important role in temporal regulation of cell migration during wound healing.Journal of Investigative Dermatology advance online publication, 10 January 2013; doi:10.1038/jid.2012.489.
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