MARIETTA BIOL 309 - LECTURE NOTES

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The actin cytoskeleton in normal and pathological cell motilityIntroductionCell motility and the actin polymerisation cycleActin binding proteins: the right protein at the right time; on the job to optimise actin turnoverModels of cell motility: variations on a themeSignal transduction mechanismsHijacking of the cytoskeletal apparatus by pathogensPathologies associated with actin dynamicsConclusionsAcknowledgementsReferencesThe International Journal of Biochemistry & Cell Biology 36 (2004) 1890–1909ReviewThe actin cytoskeleton in normal and pathological cell motilityAnja Lambrechts∗, Marleen Van Troys, Christophe AmpeDepartment of Biochemistry, Faculty of Medicine and Health Sciences, Flanders Interuniversity Institute for Biotechnology (VIB),Ghent University, A. Baertsoenkaai 3, B-9000 Gent, BelgiumAccepted 22 January 2004AbstractCell motility is crucial for tissue formation and for development of organisms. Later on cell migration remains essentialthroughout the lifetime of the organismforwound healing and immune responses. The actin cytoskeleton is the cellular enginethat drives cell motility downstream of a complex signal transduction cascade. The basic molecular machinery underlyingthe assembly and disassembly of actin filaments consists of a variety of actin binding proteins that regulate the dynamicbehavior of the cytoskeleton in response to different signals. The multitude of proteins and regulatory mechanisms partakingin this system makes it vulnerable to mutations and alterations in expression levels that ultimately may cause diseases. Themost familiar one is cancer that in later stages is characterized by active aberrant cell migration. Indeed tumor invasion andmetastasis are increasingly being associated with deregulation of the actin system.© 2004 Elsevier Ltd. All rights reserved.Keywords: Actin dynamics; Actin binding proteins; Cell migration; Cancer; InvasionContents1. Introduction ......................................................................... 18912. Cell motility and the actin polymerisation cycle ........................................ 18913. Actin binding proteins: the right protein at the right time; on the job to optimise actin turnover 18934. Models of cell motility: variations on a theme .......................................... 18975. Signal transduction mechanisms ....................................................... 18986. Hijacking of the cytoskeletal apparatus by pathogens.................................... 18997. Pathologies associated with actin dynamics............................................. 1900Abbreviations: Arp, actin related protein; BCR, breakpoint cluster region; DAD, diaphanous autoregulatory domain; DRFs,Diaphanous-related formins; EGFR, epidermal growth factor receptor; Ena, enabled; EVH, Ena/VASP homology; EVL, Ena-VASP-like;F-actin, filamentous actin; FH, formin homology; G-actin, globular actin; GAP, GTPase activating protein; GBD, GTPase binding do-main; GDI, GDP dissociation inhibitor; GEF, guanine nucleotide exchange factor; LIMK, LIM kinase; mDia, mammalian Diaphanous;Mena, mammalian enabled; PAK, p21 activated kinase; PI(3,4,5)-P3, phosphatidylinositol 3,4,5-trisphosphate; PI(4,5)-P2, phosphatidyli-nositol 4,5-bisphosphate; PI-3K, phosphatidylinositol-3 kinase; PLC, phospholipase C; PTEN, phosphatase and tensin homolog deleted onchromosome ten; SH3, Src homology 3; VASP, vasodilator stimulated phosphoprotein; WASP, Wiskott Aldrich syndrome protein; WAVE,WASP-family verprolin-homologous protein; WH, WASP homology∗Corresponding author. Tel.: +32-9-264-9332; fax: +32-9-264-9488.E-mail address: [email protected] (A. Lambrechts).1357-2725/$ – see front matter © 2004 Elsevier Ltd. All rights reserved.doi:10.1016/j.biocel.2004.01.024A. Lambrechts et al. /The International Journal of Biochemistry & Cell Biology 36 (2004) 1890–1909 18918. Conclusions ...........................................................................1903Acknowledgements.........................................................................1904References.................................................................................19041. IntroductionA variety of cellular motility processes are essen-tial throughout the life cycle of eukaryotes. Fromthe early stages of development on, cell movementis essential for the generation of the entire organism.Primary muscle cells migrate to places where limbsare formed, endothelial cells form the blood vesselwalls, neurons migrate to their proper positions andsend out axons and dendrites to find their target cells.Also in adult organisms cell motility is crucial oftenas a response to a pathological situation. Vertebrateimmune cells invade into infected tissue to eliminateinfectious agents. Fibroblasts, surrounding a wound,migrate towards each other during wound healing.Not surprisingly, many pathologies arise from aber-rant motility processes such as inappropriate immuneresponses and migration leading to chronic inflamma-tory diseases or tumor malignancy. In addition, intra-cellular pathogens have found an ingenious method touse the host cell motile machinery to spread from cellto cell. Cells move in response to signals from theirenvironment. These are sensed by transmembrane re-ceptors by which signaling cascades are initiated andultimately affect cytoskeletal and adhesive structuresof the cell. There is an intricate interplay between thedifferent cytoskeletal systems (especially actin andmicrotubule containing structures) and between thesesystems and the cell–substratum and cell–cell adhe-sive machinery. Nevertheless, the actin microfilamentsystem is still considered to be the engine of cellularFig. 1. Actin dynamics and actin-rich structures in fibroblasts and neurons. (A) Nucleation of ATP-actin monomers into filaments is enhancedby theArp2/3 complex, Ena/VASP proteins or DRFs. (B) The resulting filaments have a fast growing, barbed or +-end and a slowergrowing, pointed end. This nomenclature is based on the arrowhead pattern of actin filaments, decorated with myosin heads (Woodrumet al., 1975). The +-ends are oriented towards the membrane and incorporation of new monomers generates protrusive force. ADF/cofilinssever the filament ends and dissociate ADP-actin from the pointed end. Profilin enhances nucleotide exchange and the ATP-actin monomersare either stored in complex with thymosin ␤, or shuttled to the barbed ends as free monomers or as profilin-actin complexes.


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