[en] Actin cytoskeleton controls a vast range of cellular processes such as motility, cytokinesis,
differentiation, vesicle transport, phagocytosis, muscle contraction. A growing literature
clearly demonstrated that actin cytoskeleton can play a regulating role in several signalling
pathways. Cells tightly regulate actin dynamics through numerous specific proteins in order
to rapidly and locally respond to various stimuli. An obvious approach to determine the
involvement of actin cytoskeleton in signalling pathways is the use of actin-targeting
natural compounds. These drugs modulate actin dynamics, accelerating either polymerization
or depolymerization, through various mechanisms. This review focus on the use of
these actin-targeting drugs as tools to demonstrate the role of actin cytoskeleton in several
signal transduction pathways such as those initiated from antigen receptor in T and B cells
or those involving mitogen-activated protein kinases (MAPKs) or transcription factors NF-kB
and SRF (serum response factor). In this last case (SRF), the use of various actin-targeting
drugs participated in the elucidation of the molecular mechanism by which actin regulates
SRF-mediated transcription.
Research center :
Giga-Signal Transduction - ULiège
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Kustermans, Gaëlle ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Piette, Jacques ; Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Virologie - Immunologie - GIGA-Research
Nicholson-Dykstra S., Higgs H.N., and Harris E.S. Actin dynamics: growth from dendritic branches. Curr Biol 15 9 (2005) R346-R357
Pollard T.D. Rate constants for the reactions of ATP- and ADP-actin with the ends of actin filaments. J Cell Biol 103 6 Pt 2 (1986) 2747-2754
Vavylonis D., Yang Q., and O'Shaughnessy B. Actin polymerization kinetics, cap structure, and fluctuations. Proc Natl Acad Sci USA 102 24 (2005) 8543-8548
Pollard T.D., Blanchoin L., and Mullins R.D. Molecular mechanisms controlling actin filament dynamics in nonmuscle cells. Annu Rev Biophys Biomol Struct 29 (2000) 545-576
In: Kreis T., and Vale R. (Eds). Guidebook to the cytoskeletal and motor proteins. 2nd ed. (2005), Oxford University Press, New York
Yang C., Huang M., DeBiaso J., Pring M., Joyce M., Miki H., et al. Profilin enhances Cdc42-induced nucleation of actin polymerization. J Cell Biol 150 5 (2000) 1001-1012
Goldschmidt-Clermont P.J., Machesky L.M., Doberstein S.K., and Pollard T.D. The mechanism of interaction of human platelet profilin with actin. J Cell Biol 113 5 (1991) 1081-1089
Goley E.D., and Welch M.D. The Arp2/3 complex: an actin nucleator comes of age. Nat Rev Mol Cell Biol 7 10 (2006) 713-726
Welch M.D., and Mullins R.D. Cellular control of actin nucleation. Annu Rev Cell Dev Biol 18 (2002) 247-288
Blanchoin L., Pollard T.D., and Mullins R.D. Interactions of ADF/cofilin, Arp2/3 complex, capping protein and profilin in remodeling of branched actin filament networks. Curr Biol 10 20 (2000) 1273-1282
Staiger C.J., and Blanchoin L. Actin dynamics: old friends and new stories. Curr Opin Plant Biol 9 6 (2006) 554-562
Revenu C., Athman R., Robine S., and Louvard D. The co-workers of actin filaments: from cell structures to signals. Nat Rev Mol Cell Biol 5 8 (2004) 635-646
Wittmann T., and Waterman-Storer C.M. Cell motility: can Rho GTPases and microtubules point the way?. J Cell Sci 14 21 (2001) 3795-3803
Nanninga N. Cytokinesis in prokaryotes and eukaryotes: common principles and different solutions. Microbiol Mol Biol Rev 65 2 (2001) 319-333
Friedland J.S., Constantin D., Shaw T.C., and Stylianou E. Regulation of interleukin-8 gene expression after phagocytosis of zymosan by human monocytic cells. J Leukoc Bio 70 3 (2001) 447-454
Damiani M.T., and Colombo M.I. Microfilaments and microtubules regulate recycling from phagosomes. Exp Cell Res 289 1 (2003) 152-161
Jaffe A.B., and Hall A. Rho GTPases: biochemistry and biology. Annu Rev Cell Dev Biol 21 (2005) 247-269
Ridley A.J., and Hall A. The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell 70 3 (1992) 389-399
Charest P.G., and Firtel R.A. Big roles for small GTPases in the control of directed cell movement. Biochem J 401 2 (2007) 377-390
Smith E.R., Smedberg J.L., Rula M.E., and Xu X.X. Regulation of Ras-MAPK pathway mitogenic activity by restricting nuclear entry of activated MAPK in endoderm differentiation of embryonic carcinoma and stem cells. J Cell Biol 164 5 (2004) 689-699
Miralles F., Posern G., Zaromytidou A.I., and Treisman R. Actin dynamics control SRF activity by regulation of its coactivator MAL. Cell 113 3 (2003) 329-342
Kustermans G., El Benna J., Piette J., and Legrand-Poels S. Perturbation of actin dynamics induces NF-kappaB activation in myelomonocytic cells through an NADPH oxidase-dependent pathway. Biochem J 387 Pt 2 (2005) 531-540
Low I., and Wieland T. The interaction of phalloidin. Some of its derivatives, and of other cyclic peptides with muscle actin as studied by viscosimetry. FEBS Lett 44 3 (1974) 340-343
Wieland T., and Faulstich H. The action of phalloidin. Curr Probl Clin Biochem 7 (1977) 11-14
Crews P., Manes L.V., Boehler M., and Jasplakinolide. a cyclodepsipeptide from the marine sponge, Jaspis sp. Tetrahedron Lett 27 (1986) 2797-2800
Zampella A., Giannini C., Debitus C., Roussakis C., and D'Auria M.V. New jaspamide derivatives from the marine sponge Jaspis splendans collected in Vanuatu. J Nat Prod 62 2 (1999) 332-334
Bubb M.R., Spector I., Beyer B.B., and Fosen K.M. Effects of jasplakinolide on the kinetics of actin polymerisation. An explanation for certain in vivo observations. J Biol Chem 275 7 (2000) 5163-5170
Shurety W., Stewart N.L., and Stow J.L. Fluid-phase markers in the basolateral endocytic pathway accumulate in response to the actin assembly-promoting drug Jasplakinolide. Mol Biol Cell 9 4 (1998) 957-975
Bubb M.R., Senderowicz A.M., Sausville E.A., Duncan K.L., Korn E.D., and Jasplakinolide. a cytotoxic natural product, induces actin polymerization and competitively inhibits the binding of phalloidin to F-actin. J Biol Chem 269 21 (1994) 14869-14871
Allingham J.S., Klenchin V.A., and Rayment I. Acting-targeting natural products: structures, properties and mechanisms of action. Cell Mol Life Sci 63 18 (2006) 2119-2134
Spector I., Shochet N.R., Kashman Y., and Groweiss A. Latrunculins: novel marine toxins that disrupt microfilament organization in cultured cells. Science 219 4584 (1983) 493-495
Vilozny B., Amagata T., Mooberry S.L., and Crews P. A new dimension to the biosynthetic products isolated from the sponge Negombata magnifica. J Nat Prod 67 6 (2004) 1055-1057
Coue M., Brenner S.L., Spector I., and Korn E.D. Inhibition of actin polymerization by latrunculin A. FEBS Lett 213 2 (1987) 316-318
Spector I., Braet F., Shochet N.R., and Bubb M.R. New anti-actin drugs in the study of the organization and function of the actin cytoskeleton. Microsc Res Technol 47 1 (1999) 18-37
Yahara I., Harada F., Sekita S., Yoshihira K., and Natori S. Correlation between effects of 24 different cytochalasins on cellular structures and cellular events and those on actin in vitro. J Cell Biol 92 1 (1982) 69-78
Cooper J.A. Effects of cytochalasin and phalloidin on actin. J Cell Biol 105 4 (1987) 1473-1478
Sampath P., and Pollard T.D. Effects of cytochalasin, phalloidin, and pH on the elongation of actin filaments. Biochemistry 30 7 (1991) 1973-1980
Rampal A.L., Pinokofsky H.B., and Jung Y. Structure of cytochalasins and cytochalasin B binding site in human erythrocyte membranes. Biochemistry 19 4 (1980) 679-683
Bubb M.R., Spector I., Bershadsky A.D., Korn E.D., and Swinholide. A is a microfilament disrupting marine toxin that stabilizes actin dimers and severs actin filaments. J Biol Chem 270 8 (1995) 3463-3466
Wange R.L., and Samelson L.E. Complex complexes: signalling at the TCR. Immunity 5 3 (1996) 197-205
Yokosuka T., Sakata-Sogawa K., Kobayashi W., Hiroshima M., Hashimoto-Tane A., Tokunaga M., et al. Newly generated T cell receptor microclusters initiate and sustain T cell activation by recruitment of Zap70 and SLP-76. Nat Immunol 6 12 (2005) 1253-1262
Carrasco Y.R., and Batista F.D. B cell recognition of membrane-bound antigen: an exquisite way of sensing ligands. Curr Opin Immunol 18 3 (2006) 286-291
Zandi E., Rothwarf D.M., Delhase M., Hayakawa M., Karin M., and Wienands J. B cell signalling. Introduction. Int Rev Immunol 20 6 (2001) 675-678
Tskvitaria-Fuller I., Rozelle A.L., Yin H.L., and Wülfing C. Regulation of sustained actin dynamics by the TCR and costimulation as a mechanism of receptor localization. J Immunol 171 5 (2003) 2287-2295
Cemerski S., and Shaw A. Immune synapses in T-cell activation. Curr Opin Immunol 18 3 (2006) 298-304
Bunnell S.C., Kapoor V., Trible R.P., Zhang W., and Samelson L.E. Dynamic actin polymerization drives T cell receptor-induced spreading: a role for the signal transduction adaptor LAT. Immunity 14 3 (2001) 315-329
Valitutti S., Dessing M., Aktories K., Gallati H., and Lanzavecchia A. Different responses are elicited in cytotoxic T lymphocytes by different levels of T cell receptor occupancy. J Exp Med 183 4 (1996) 1917-1921
Grakoui A., Bromley S.K., Sumen C., Davis M.M., Shaw A.S., Allen P.M., et al. The immunological synapse: a molecular machine controlling T cell activation. Science 285 5425 (1999) 221-227
Shen A., Puente L.G., and Ostergaard H.L. Tyrosine kinase activity and remodelling of the actin cytoskeleton are co-temporally required for degranulation by cytotoxic T lymphocytes. Immunology 116 2 (2005) 276-286
Campi G., Varma R., and Dustin M.L. Actin and agonist MHC-peptide complex-dependent T cell receptor microclusters as scaffolds for signaling. J Exp Med 202 8 (2005) 1031-1036
Hao S., and August A. Actin depolymerization transduces the strength of B-cell receptor stimulation. Mol Biol Cell 16 5 (2005) 2275-2284
Brown B.K., and Song W. The actin cytoskeleton is required for the trafficking of the B cell antigen receptor to the late endosomes. Traffic 2 6 (2001) 414-427
Pizzo P., and Viola A. Lymphocyte lipid rafts: structure and function. Curr Opin Immunol 15 3 (2003) 255-260
Gupta N., and Defranco A.L. Lipid rafts and B cell signaling. Semin Cell Dev Biol 18 5 (2007) 616-626
Posada J., and Cooper J.A. Requirements for phosphorylation of MAP kinase during meiosis in Xenopus oocytes. Science 255 (1992) 212-215
Kosako H., Nishida E., and Gotoh Y. cDNA cloning of MAP kinase reveals kinase cascade pathways in yeasts to vertebrates. EMBO J 12 (1993) 787-794
Robinson M.J., and Cobb M.H. Mitogen-activated protein kinase pathways. Curr Opin Cell Biol 9 2 (1997) 180-186
Johnson G.L., and Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298 5600 (2002) 1911-1912
Adachi M., Fukuda M., and Nishida E. Two co-existing mechanisms for nuclear import of MAP kinase: passive diffusion of a monomer and active transport of a dimmer. EMBO J 18 19 (1999) 347-358
Khohlatchev A.V., Canagarajah B., Wilsbacher J., Robinson M., Atkinson M., Goldsmith E., et al. Phosphorylation of the MAP kinase ERK2 promotes its homodimerization and nuclear translocation. Cell 93 4 (1998) 605-615
Matsubayashi Y., Fukuda M., and Nishida E. Evidence for existence of a nuclear pore complex-mediated, cytosol-independent pathway of nuclear translocation of ERK MAP kinase in permeabilized cells. J Biol Chem 276 45 (2001) 41755-41760
Botteri F.M., Ballmer-Hofer K., Rajput B., and Nagamine Y. Disruption of cytoskeletal structures results in the induction of the urokinase-type plasminogen activator gene expression. J Biol Chem 265 22 (1990) 13327-13334
Saksela O., and Rifkin D.B. The opposing effects of basic fibroblast growth factor and transforming growth factor beta on the regulation of plasminogen activator activity in capillary endothelial cells. J Cell Biol 105 2 (1987) 957-963
Irigoyen J.P., Besser D., and Nagamine Y. Cytoskeleton reorganization induces the urokinase-type plasminogen activator gene via the Ras/extracellular signal-regulated kinase (ERK) signaling pathway. J Biol Chem 272 3 (1997) 1904-1909
Samarakoon R., and Higgins P.J. MEK/ERK pathway mediates cell-shape-dependent plasminogen activator inhibitor type 1 gene expression upon drug-induced disruption of the microfilament and microtubule networks. J Cell Sci 115 Pt 15 (2002) 3093-3103
Higgins P.J., Ryan M.P., and Providence K.M. Induced expression of p52(PAI-1) in normal rat kidney cells by the microfilament-disrupting agent cytochalasin D. J Cell Physiol 159 1 (1994) 187-195
Kawamura S., Miyamoto S., and Brown J.H. Initiation and transduction of stretch-induced RhoA and Rac1 activation through caveolae: cytoskeletal regulation of ERK translocation. J Biol Chem 278 33 (2003) 31111-31117
Aplin A.E., Stewart S.A., Assoian R.K., and Juliano R.L. Integrin-mediated adhesion regulates ERK nuclear translocation and phosphorylation of Elk-1. J Cell Biol 153 2 (2001) 273-282
Ingram A.J., James L., Cai L., Thai K., Ly H., and Scholey J.W. NO inhibits stretch-induced MAPK activity by cytoskeletal disruption. J Biol Chem 275 51 (2000) 40301-40306
Ono K., and Han J. The p38 signal transduction pathway: activation and function. Cell Signal 12 1 (2000) 1-13
Kim S.J., Hwang S.G., Kim I.C., and Chun J.S. Actin cytoskeletal architecture regulates nitric oxide-induced apoptosis, dedifferentiation, and cyclooxygenase-2 expression in articular chondrocytes via mitogen-activated protein kinase and protein kinase C pathways. J Biol Chem 278 43 (2003) 42448-42456
Németh Z.H., Deitch E.A., Davidson M.T., Szabó C., Vizi E.S., and Haskó G. Disruption of the actin cytoskeleton results in nuclear factor-kappaB activation and inflammatory mediator production in cultured human intestinal epithelial cells. J Cell Physiol 200 1 (2004) 71-81
Khurana A. Dey CS. p38 MAPK interacts with actin and modulates filament assembly during skeletal muscle differentiation. Differentiation 71 1 (2003) 42-50
Guay J., Lambert H., Gingras-Breton G., Lavoie J.N., Huot J., and Landry J. Regulation of actin filament dynamics by p38 map kinase-mediated phosphorylation of heat shock protein 27. J Cell Sci 110 Pt 3 (1997) 357-368
Tsakiridis T., Bergman A., Somwar R., Taha C., Aktories K., Cruz T.F., et al. Actin filaments facilitate insulin activation of the src and collagen homologous/mitogen activated protein kinase pathway leading to DNA synthesis and c-fos expression. J Biol Chem 273 43 (1998) 28322-28331
Cheatham B., and Kahn C.R. Insulin action and the insulin signaling network. Endocr Rev 16 2 (1995) 117-142
Yenush L., and White M.F. The IRS-signaling system during insulin and cytokine action. Bioessays 19 6 (1997) 491-500
Whites M.F., and Kahn C.R. The insulin signaling system. J Biol Chem 269 1 (1994) 1-4
Seufferlein T., Withers D.J., Mann D., and Rozengurt E. Dissociation of mitogen-activated protein kinase activation from p125 focal adhesion kinase tyrosine phosphorylation in Swiss 3T3 cells stimulated by bombesin, lysophosphatidic acid, and platelet-derived growth factor. Mol Biol Cell 7 12 (1996) 1865-1875
Ghosh S., May M.J., and Kopp E.B. NF-κB and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 16 (1998) 225-260
Baldwin A.S. The NF-κB and IκB proteins: new discoveries and insights. Annu Rev Immunol 14 (1996) 649-683
Karin M., and Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu Rev Immunol 18 (2000) 621-663
Hayden M.S., and Ghosh S. Signaling to NF-kappaB. Genes Dev 18 18 (2004) 2195-2224
The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation. Cell 1997;91(2):243-52.
Ghosh S., and Karin M. Missing pieces in the NF-κB puzzle. Cell 109 (2002) S81-S96
Rosette C., and Karin M. Cytoskeletal control of gene expression: depolymerization of microtubules activates NF-kappa B. J Cell Biol 128 6 (1995) 1111-1119
Bourgarel-Rey V., Vallee S., Rimet O., Champion D., Braguer D., Desobry A., et al. Involvement of nuclear factor kappaB in c-Myc induction by tubulin polymerization inhibitors. Mol Pharmacol 59 5 (2001) 1165-1170
Algul H., Tando Y., Beil M., Weber C.K., Von Weyhern C., Schneider G., et al. Different modes of NF-kappaB/Rel activation in pancreatic lobules. Am J Physiol Gastrointest Liver Physiol 283 2 (2001) G270-G281
Spencer W., Kwon H., Crepieux P., Leclerc N., Lin R., and Hiscott J. Taxol selectively blocks microtubule dependent NF-kappaB activation by phorbol ester via inhibition of IkappaBalpha phosphorylation and degradation. Oncogene 18 2 (1999) 495-505
Are A.F., Galkin V.E., Pospelova T.V., and Pinaev G.P. The p65/RelA subunit of NF-kappaB interacts with actin-containing structures. Exp Cell Res 256 2 (2000) 533-544
Chaqour B., Yang R., and Sha Q. Mechanical stretch modulates the promoter activity of the profibrotic factor CCN2 through increased actin polymerization and NF-kappaB activation. J Biol Chem 281 29 (2006) 20608-20622
Mikenberg I., Widera D., Kaus A., Kaltschmidt B., and Kaltschmidt C. TNF-alpha mediated transport of NF-kappaB to the nucleus is independent of the cytoskeleton-based transport system in non-neuronal cells. Eur J Cell Biol 85 6 (2006) 529-536
Mackenzie G.G., Keen C.L., and Oteiza P.I. Microtubules are required for NF-kappaB nuclear translocation in neuroblastoma IMR-32 cells: modulation by zinc. J Neurochem 99 2 (2006) 402-415
Fazal F., Minhajuddin M., Bijli K.M., McGrath J.L., and Rahman A. Evidence for actin cytoskeleton-dependent and -independent pathways for RelA/p65 nuclear translocation in endothelial cells. J Biol Chem 282 6 (2007) 3940-3950
Posern G., and Treisman R. Actin's together: serum response factor, its cofactors and the link to signal transduction. Trends Cell Biol 16 11 (2006) 588-596
Miano J.M., Long X., and Fujiwara K. Serum response factor: master regulator of the actin cytoskeleton and contractile apparatus. Am J Physiol Cell Physiol 292 1 (2007) C70-81
Minty A., and Kedes L. Upstream regions of the human cardiac actin gene that modulate its transcription in muscle cells: presence of an evolutionarily conserved repeated motif. Mol Cell Biol 6 6 (1986) 2125-2136
Buchwalter G., Gross C., and Wasylyk B. Ets ternary complex transcription factors. Gene 324 (2004) 1-14
Hill C.S., Wynne J., and Treisman R. The Rho family GTPases RhoA, Rac1, and CDC42Hs regulate transcriptional activation by SRF. Cell 81 7 (1995) 1159-1170
Wang D.Z., Li S., Hockemeyer D., Sutherland L., Wang Z., Schratt G., et al. Potentiation of serum response factor activity by a family of myocardin-related transcription factors. Proc Natl Acad Sci USA 99 23 (2002) 14855-14860
Treisman R. Ternary complex factors: growth factor regulated transcriptional activators. Curr Opin Genet Dev 4 1 (1994) 96-101
Sotiropoulos A., Gineitis D., Copeland J., and Treisman R. Signal-regulated activation of serum response factor is mediated by changes in actin dynamics. Cell 98 2 (1999) 159-166
Posern G., Miralles F., Guettler S., and Treisman R. Mutant actins that stabilise F-actin use distinct mechanisms to activate the SRF coactivator MAL. EMBO J 23 20 (2004) 3973-3983
Settleman J. A nuclear MAL-function links Rho to SRF. Mol Cell 11 5 (2003) 1121-1123
Kuwahara K., Barrientos T., Pipes G.C., Li S., and Olson E.N. Muscle-specific signaling mechanism that links actin dynamics to serum response factor. Mol Cell Biol 25 8 (2005) 3173-3181
Vartiainen M.K., Guettler S., Larijani B., and Treisman R. Nuclear actin regulates dynamic subcellular localization and activity of the SRF cofactor MAL. Science 316 5832 (2007) 1749-1752
Liu H.W., Halayko A.J., Fernandes D.J., Harmon G.S., McCauley J.A., Kocieniewski P., et al. The RhoA/Rho kinase pathway regulates nuclear localization of serum response factor. Am J Respir Cell Mol Biol 29 1 (2003) 39-47