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Cellular and pathophysiological consequences of Arp2/3 complex inhibition: role of inhibitory proteins and pharmacological compounds

Cellular and Molecular Life Sciences volume 76, pages 3349–3361 (2019)Cite this article

Abstract

The actin-related protein complex 2/3 (Arp2/3) generates branched actin networks important for many cellular processes such as motility, vesicular trafficking, cytokinesis, and intercellular junction formation and stabilization. Activation of Arp2/3 requires interaction with actin nucleation-promoting factors (NPFs). Regulation of Arp2/3 activity is achieved by endogenous inhibitory proteins through direct binding to Arp2/3 and competition with NPFs or by binding to Arp2/3-induced actin filaments and disassembly of branched actin networks. Arp2/3 inhibition has recently garnered more attention as it has been associated with attenuation of cancer progression, neurotoxic effects during drug abuse, and pathogen invasion of host cells. In this review, we summarize current knowledge on expression, inhibitory mechanisms and function of endogenous proteins able to inhibit Arp2/3 such as coronins, GMFs, PICK1, gadkin, and arpin. Moreover, we discuss cellular consequences of pharmacological Arp2/3 inhibition.

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References

  1. Garcia-Ponce A, Citalan-Madrid AF, Velazquez-Avila M, Vargas-Robles H, Schnoor M (2015) The role of actin-binding proteins in the control of endothelial barrier integrity. Thromb Haemost 113:20–36

    Article  PubMed  Google Scholar 

  2. Rouiller I, Xu XP, Amann KJ, Egile C, Nickell S, Nicastro D, Li R, Pollard TD, Volkmann N, Hanein D (2008) The structural basis of actin filament branching by the Arp2/3 complex. J Cell Biol 180:887–895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Pizarro-Cerda J, Chorev DS, Geiger B, Cossart P (2017) The diverse family of Arp2/3 complexes. Trends Cell Biol 27:93–100

    Article  CAS  PubMed  Google Scholar 

  4. Abella JV, Galloni C, Pernier J, Barry DJ, Kjaer S, Carlier MF, Way M (2016) Isoform diversity in the Arp2/3 complex determines actin filament dynamics. Nat Cell Biol 18:76–86

    Article  CAS  PubMed  Google Scholar 

  5. Chorev DS, Moscovitz O, Geiger B, Sharon M (2014) Regulation of focal adhesion formation by a vinculin-Arp2/3 hybrid complex. Nat Commun 5:3758

    Article  PubMed  Google Scholar 

  6. Yae K, Keng VW, Koike M, Yusa K, Kouno M, Uno Y, Kondoh G, Gotow T, Uchiyama Y, Horie K, Takeda J (2006) Sleeping beauty transposon-based phenotypic analysis of mice: lack of Arpc3 results in defective trophoblast outgrowth. Mol Cell Biol 26:6185–6196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Suraneni P, Rubinstein B, Unruh JR, Durnin M, Hanein D, Li R (2012) The Arp2/3 complex is required for lamellipodia extension and directional fibroblast cell migration. J Cell Biol 197:239–251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Rotty JD, Wu C, Bear JE (2013) New insights into the regulation and cellular functions of the ARP2/3 complex. Nat Rev Mol Cell Biol 14:7–12

    Article  CAS  PubMed  Google Scholar 

  9. Molinie N, Gautreau A (2018) The Arp2/3 regulatory system and its deregulation in cancer. Physiol Rev 98:215–238

    Article  CAS  PubMed  Google Scholar 

  10. Chan KT, Creed SJ, Bear JE (2011) Unraveling the enigma: progress towards understanding the coronin family of actin regulators. Trends Cell Biol 21:481–488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Humphries CL, Balcer HI, D’Agostino JL, Winsor B, Drubin DG, Barnes G, Andrews BJ, Goode BL (2002) Direct regulation of Arp2/3 complex activity and function by the actin binding protein coronin. J Cell Biol 159:993–1004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Liu SL, Needham KM, May JR, Nolen BJ (2011) Mechanism of a concentration-dependent switch between activation and inhibition of Arp2/3 complex by coronin. J Biol Chem 286:17039–17046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cai L, Marshall TW, Uetrecht AC, Schafer DA, Bear JE (2007) Coronin 1B coordinates Arp2/3 complex and cofilin activities at the leading edge. Cell 128:915–929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Cai L, Makhov AM, Schafer DA, Bear JE (2008) Coronin 1B antagonizes cortactin and remodels Arp2/3-containing actin branches in lamellipodia. Cell 134:828–842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Xavier CP, Rastetter RH, Blomacher M, Stumpf M, Himmel M, Morgan RO, Fernandez MP, Wang C, Osman A, Miyata Y, Gjerset RA, Eichinger L, Hofmann A, Linder S, Noegel AA, Clemen CS (2012) Phosphorylation of CRN2 by CK2 regulates F-actin and Arp2/3 interaction and inhibits cell migration. Sci Rep 2:241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Park M, Kim HJ, Lim B, Wylegala A, Toborek M (2013) Methamphetamine-induced occludin endocytosis is mediated by the Arp2/3 complex-regulated actin rearrangement. J Biol Chem 288:33324–33334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kim GY, Park JH, Kim H, Lim HJ, Park HY (2016) Coronin 1B serine 2 phosphorylation by p38alpha is critical for vascular endothelial growth factor-induced migration of human umbilical vein endothelial cells. Cell Signal 28:1817–1825

    Article  CAS  PubMed  Google Scholar 

  18. Shiow LR, Roadcap DW, Paris K, Watson SR, Grigorova IL, Lebet T, An J, Xu Y, Jenne CN, Foger N, Sorensen RU, Goodnow CC, Bear JE, Puck JM, Cyster JG (2008) The actin regulator coronin 1A is mutant in a thymic egress-deficient mouse strain and in a patient with severe combined immunodeficiency. Nat Immunol 9:1307–1315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Haraldsson MK, Louis-Dit-Sully CA, Lawson BR, Sternik G, Santiago-Raber ML, Gascoigne NR, Theofilopoulos AN, Kono DH (2008) The lupus-related Lmb3 locus contains a disease-suppressing Coronin-1A gene mutation. Immunity 28:40–51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Siegmund K, Zeis T, Kunz G, Rolink T, Schaeren-Wiemers N, Pieters J (2011) Coronin 1-mediated naive T cell survival is essential for the development of autoimmune encephalomyelitis. J Immunol 186:3452–3461

    Article  CAS  PubMed  Google Scholar 

  21. Xu XJ, Tang YM (2015) Coronin-1a is a potential therapeutic target for activated T cell-related immune disorders. APMIS 123:89–91

    Article  CAS  PubMed  Google Scholar 

  22. Tchang VS, Mekker A, Siegmund K, Karrer U, Pieters J (2013) Diverging role for coronin 1 in antiviral CD4+ and CD8+ T cell responses. Mol Immunol 56:683–692

    Article  CAS  PubMed  Google Scholar 

  23. Kim GY, Kim H, Lim HJ, Park HY (2015) Coronin 1A depletion protects endothelial cells from TNFalpha-induced apoptosis by modulating p38beta expression and activation. Cell Signal 27:1688–1693

    Article  CAS  PubMed  Google Scholar 

  24. Goode BL, Sweeney MO, Eskin JA (2018) GMF as an actin network remodeling factor. Trends Cell Biol 28:749–760

    Article  CAS  PubMed  Google Scholar 

  25. Ikeda K, Kundu RK, Ikeda S, Kobara M, Matsubara H, Quertermous T (2006) Glia maturation factor-gamma is preferentially expressed in microvascular endothelial and inflammatory cells and modulates actin cytoskeleton reorganization. Circ Res 99:424–433

    Article  CAS  PubMed  Google Scholar 

  26. Gandhi M, Smith BA, Bovellan M, Paavilainen V, Daugherty-Clarke K, Gelles J, Lappalainen P, Goode BL (2010) GMF is a cofilin homolog that binds Arp2/3 complex to stimulate filament debranching and inhibit actin nucleation. Curr Biol 20:861–867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ydenberg CA, Padrick SB, Sweeney MO, Gandhi M, Sokolova O, Goode BL (2013) GMF severs actin-Arp2/3 complex branch junctions by a cofilin-like mechanism. Curr Biol 23:1037–1045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Luan Q, Nolen BJ (2013) Structural basis for regulation of Arp2/3 complex by GMF. Nat Struct Mol Biol 20:1062–1068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Boczkowska M, Rebowski G, Dominguez R (2013) Glia maturation factor (GMF) interacts with Arp2/3 complex in a nucleotide state-dependent manner. J Biol Chem 288:25683–25688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Guo S, Sokolova OS, Chung J, Padrick S, Gelles J, Goode BL (2018) Abp1 promotes Arp2/3 complex-dependent actin nucleation and stabilizes branch junctions by antagonizing GMF. Nat Commun 9:2895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Aerbajinai W, Liu L, Chin K, Zhu J, Parent CA, Rodgers GP (2011) Glia maturation factor-gamma mediates neutrophil chemotaxis. J Leukoc Biol 90:529–538

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lippert DN, Wilkins JA (2012) Glia maturation factor gamma regulates the migration and adherence of human T lymphocytes. BMC Immunol 13:21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Aerbajinai W, Liu L, Zhu J, Kumkhaek C, Chin K, Rodgers GP (2016) Glia maturation factor-gamma regulates monocyte migration through modulation of beta1-integrin. J Biol Chem 291:8549–8564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zuo P, Fu Z, Tao T, Ye F, Chen L, Wang X, Lu W, Xie X (2013) The expression of glia maturation factors and the effect of glia maturation factor-gamma on angiogenic sprouting in zebrafish. Exp Cell Res 319:707–717

    Article  CAS  PubMed  Google Scholar 

  35. Wang T, Cleary RA, Wang R, Tang DD (2014) Glia maturation factor-gamma phosphorylation at Tyr-104 regulates actin dynamics and contraction in human airway smooth muscle. Am J Respir Cell Mol Biol 51:652–659

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Haynes EM, Asokan SB, King SJ, Johnson HE, Haugh JM, Bear JE (2015) GMFbeta controls branched actin content and lamellipodial retraction in fibroblasts. J Cell Biol 209:803–812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zaheer A, Zaheer S, Thangavel R, Wu Y, Sahu SK, Yang B (2008) Glia maturation factor modulates beta-amyloid-induced glial activation, inflammatory cytokine/chemokine production and neuronal damage. Brain Res 1208:192–203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Thangavel R, Kempuraj D, Stolmeier D, Anantharam P, Khan M, Zaheer A (2013) Glia maturation factor expression in entorhinal cortex of Alzheimer’s disease brain. Neurochem Res 38:1777–1784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Stolmeier D, Thangavel R, Anantharam P, Khan MM, Kempuraj D, Zaheer A (2013) Glia maturation factor expression in hippocampus of human Alzheimer’s disease. Neurochem Res 38:1580–1589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zaheer S, Wu Y, Sahu SK, Zaheer A (2010) Overexpression of glia maturation factor reinstates susceptibility to myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in glia maturation factor deficient mice. Neurobiol Dis 40:593–598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Imai R, Asai K, Hanai J, Takenaka M (2015) Transgenic mice overexpressing glia maturation factor-beta, an oxidative stress inducible gene, show premature aging due to Zmpste24 down-regulation. Aging (Albany NY) 7:486–499

    Article  CAS  Google Scholar 

  42. Li YL, Ye F, Cheng XD, Hu Y, Zhou CY, Lu WG, Xie X (2010) Identification of glia maturation factor beta as an independent prognostic predictor for serous ovarian cancer. Eur J Cancer 46:2104–2118

    Article  CAS  PubMed  Google Scholar 

  43. Kuang XY, Jiang XF, Chen C, Su XR, Shi Y, Wu JR, Zhang P, Zhang XL, Cui YH, Ping YF, Bian XW (2016) Expressions of glia maturation factor-beta by tumor cells and endothelia correlate with neovascularization and poor prognosis in human glioma. Oncotarget 7:85750–85763

    PubMed  Google Scholar 

  44. Neubrand VE, Will RD, Mobius W, Poustka A, Wiemann S, Schu P, Dotti CG, Pepperkok R, Simpson JC (2005) Gamma-BAR, a novel AP-1-interacting protein involved in post-Golgi trafficking. EMBO J 24:1122–1133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Schmidt MR, Maritzen T, Kukhtina V, Higman VA, Doglio L, Barak NN, Strauss H, Oschkinat H, Dotti CG, Haucke V (2009) Regulation of endosomal membrane traffic by a Gadkin/AP-1/kinesin KIF5 complex. Proc Natl Acad Sci USA 106:15344–15349

    Article  PubMed  Google Scholar 

  46. Maritzen T, Zech T, Schmidt MR, Krause E, Machesky LM, Haucke V (2012) Gadkin negatively regulates cell spreading and motility via sequestration of the actin-nucleating ARP2/3 complex. Proc Natl Acad Sci USA 109:10382–10387

    Article  PubMed  Google Scholar 

  47. Laulagnier K, Schieber NL, Maritzen T, Haucke V, Parton RG, Gruenberg J (2011) Role of AP1 and Gadkin in the traffic of secretory endo-lysosomes. Mol Biol Cell 22:2068–2082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Schachtner H, Weimershaus M, Stache V, Plewa N, Legler DF, Hopken UE, Maritzen T (2015) Loss of Gadkin affects dendritic cell migration in vitro. PLoS One 10:e0143883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Mertins P, Przybylski D, Yosef N, Qiao J, Clauser K, Raychowdhury R, Eisenhaure TM, Maritzen T, Haucke V, Satoh T, Akira S, Carr SA, Regev A, Hacohen N, Chevrier N (2017) An integrative framework reveals signaling-to-transcription events in Toll-like receptor signaling. Cell Rep 19:2853–2866

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Staudinger J, Zhou J, Burgess R, Elledge SJ, Olson EN (1995) PICK1: a perinuclear binding protein and substrate for protein kinase C isolated by the yeast two-hybrid system. J Cell Biol 128:263–271

    Article  CAS  PubMed  Google Scholar 

  51. Staudinger J, Lu J, Olson EN (1997) Specific interaction of the PDZ domain protein PICK1 with the COOH terminus of protein kinase C-alpha. J Biol Chem 272:32019–32024

    Article  CAS  PubMed  Google Scholar 

  52. Peter BJ, Kent HM, Mills IG, Vallis Y, Butler PJ, Evans PR, McMahon HT (2004) BAR domains as sensors of membrane curvature: the amphiphysin BAR structure. Science 303:495–499

    Article  CAS  PubMed  Google Scholar 

  53. Rocca DL, Martin S, Jenkins EL, Hanley JG (2008) Inhibition of Arp2/3-mediated actin polymerization by PICK1 regulates neuronal morphology and AMPA receptor endocytosis. Nat Cell Biol 10:259–271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Nakamura Y, Wood CL, Patton AP, Jaafari N, Henley JM, Mellor JR, Hanley JG (2011) PICK1 inhibition of the Arp2/3 complex controls dendritic spine size and synaptic plasticity. EMBO J 30:719–730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Anggono V, Clem RL, Huganir RL (2011) PICK1 loss of function occludes homeostatic synaptic scaling. J Neurosci 31:2188–2196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Haglerod C, Kapic A, Boulland JL, Hussain S, Holen T, Skare O, Laake P, Ottersen OP, Haug FM, Davanger S (2009) Protein interacting with C kinase 1 (PICK1) and GluR2 are associated with presynaptic plasma membrane and vesicles in hippocampal excitatory synapses. Neuroscience 158:242–252

    Article  CAS  PubMed  Google Scholar 

  57. Mignogna ML, Giannandrea M, Gurgone A, Fanelli F, Raimondi F, Mapelli L, Bassani S, Fang H, Van Anken E, Alessio M, Passafaro M, Gatti S, Esteban JA, Huganir R, D’Adamo P (2015) The intellectual disability protein RAB39B selectively regulates GluA2 trafficking to determine synaptic AMPAR composition. Nat Commun 6:6504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Pinheiro PS, Jansen AM, de Wit H, Tawfik B, Madsen KL, Verhage M, Gether U, Sorensen JB (2014) The BAR domain protein PICK1 controls vesicle number and size in adrenal chromaffin cells. J Neurosci 34:10688–10700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Fiuza M, Rostosky CM, Parkinson GT, Bygrave AM, Halemani N, Baptista M, Milosevic I, Hanley JG (2017) PICK1 regulates AMPA receptor endocytosis via direct interactions with AP2 alpha-appendage and dynamin. J Cell Biol 216:3323–3338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Hanley JG (2018) The regulation of AMPA receptor endocytosis by dynamic protein–protein interactions. Front Cell Neurosci 12:362

    Article  PubMed  PubMed Central  Google Scholar 

  61. Rocca DL, Amici M, Antoniou A, Blanco Suarez E, Halemani N, Murk K, McGarvey J, Jaafari N, Mellor JR, Collingridge GL, Hanley JG (2013) The small GTPase Arf1 modulates Arp2/3-mediated actin polymerization via PICK1 to regulate synaptic plasticity. Neuron 79:293–307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Murk K, Blanco Suarez EM, Cockbill LM, Banks P, Hanley JG (2013) The antagonistic modulation of Arp2/3 activity by N-WASP, WAVE2 and PICK1 defines dynamic changes in astrocyte morphology. J Cell Sci 126:3873–3883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Madasu Y, Yang C, Boczkowska M, Bethoney KA, Zwolak A, Rebowski G, Svitkina T, Dominguez R (2015) PICK1 is implicated in organelle motility in an Arp2/3 complex-independent manner. Mol Biol Cell 26:1308–1322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Sathe M, Muthukrishnan G, Rae J, Disanza A, Thattai M, Scita G, Parton RG, Mayor S (2018) Small GTPases and BAR domain proteins regulate branched actin polymerisation for clathrin and dynamin-independent endocytosis. Nat Commun 9:1835

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Reymond N, Garrido-Urbani S, Borg JP, Dubreuil P, Lopez M (2005) PICK-1: a scaffold protein that interacts with Nectins and JAMs at cell junctions. FEBS Lett 579:2243–2249

    Article  CAS  PubMed  Google Scholar 

  66. Son J, Park MS, Park I, Lee HK, Lee SH, Kang B, Min BH, Ryoo J, Lee S, Bae JS, Kim SH, Park MJ, Lee HS (2014) Pick1 modulates ephrinB1-induced junctional disassembly through an association with ephrinB1. Biochem Biophys Res Commun 450:659–665

    Article  CAS  PubMed  Google Scholar 

  67. Xiao N, Kam C, Shen C, Jin W, Wang J, Lee KM, Jiang L, Xia J (2009) PICK1 deficiency causes male infertility in mice by disrupting acrosome formation. J Clin Investig 119:802–812

    Article  CAS  PubMed  Google Scholar 

  68. He J, Xia M, Tsang WH, Chow KL, Xia J (2015) ICA1L forms BAR-domain complexes with PICK1 and is crucial for acrosome formation in spermiogenesis. J Cell Sci 128:3822–3836

    Article  CAS  PubMed  Google Scholar 

  69. Liu G, Shi QW, Lu GX (2010) A newly discovered mutation in PICK1 in a human with globozoospermia. Asian J Androl 12:556–560

    Article  PubMed  PubMed Central  Google Scholar 

  70. Zhang B, Cao W, Zhang F, Zhang L, Niu R, Niu Y, Fu L, Hao X, Cao X (2010) Protein interacting with C alpha kinase 1 (PICK1) is involved in promoting tumor growth and correlates with poor prognosis of human breast cancer. Cancer Sci 101:1536–1542

    Article  CAS  PubMed  Google Scholar 

  71. Wang W, Wyckoff JB, Frohlich VC, Oleynikov Y, Huttelmaier S, Zavadil J, Cermak L, Bottinger EP, Singer RH, White JG, Segall JE, Condeelis JS (2002) Single cell behavior in metastatic primary mammary tumors correlated with gene expression patterns revealed by molecular profiling. Cancer Res 62:6278–6288

    CAS  PubMed  Google Scholar 

  72. Zheng HC, Zheng YS, Li XH, Takahashi H, Hara T, Masuda S, Yang XH, Guan YF, Takano Y (2008) Arp2/3 overexpression contributed to pathogenesis, growth and invasion of gastric carcinoma. Anticancer Res 28:2225–2232

    PubMed  Google Scholar 

  73. Rauhala HE, Teppo S, Niemela S, Kallioniemi A (2013) Silencing of the ARP2/3 complex disturbs pancreatic cancer cell migration. Anticancer Res 33:45–52

    CAS  PubMed  Google Scholar 

  74. Liu Z, Yang X, Chen C, Liu B, Ren B, Wang L, Zhao K, Yu S, Ming H (2013) Expression of the Arp2/3 complex in human gliomas and its role in the migration and invasion of glioma cells. Oncol Rep 30:2127–2136

    Article  CAS  PubMed  Google Scholar 

  75. Massague J (2008) TGFbeta in cancer. Cell 134:215–230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Zhao B, Wang Q, Du J, Luo S, Xia J, Chen YG (2012) PICK1 promotes caveolin-dependent degradation of TGF-beta type I receptor. Cell Res 22:1467–1478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Cockbill LM, Murk K, Love S, Hanley JG (2015) Protein interacting with C kinase 1 suppresses invasion and anchorage-independent growth of astrocytic tumor cells. Mol Biol Cell 26:4552–4561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Hong CJ, Liao DL, Shih HL, Tsai SJ (2004) Association study of PICK1 rs3952 polymorphism and schizophrenia. NeuroReport 15:1965–1967

    Article  CAS  PubMed  Google Scholar 

  79. Fujii K, Maeda K, Hikida T, Mustafa AK, Balkissoon R, Xia J, Yamada T, Ozeki Y, Kawahara R, Okawa M, Huganir RL, Ujike H, Snyder SH, Sawa A (2006) Serine racemase binds to PICK1: potential relevance to schizophrenia. Mol Psychiatry 11:150–157

    Article  CAS  PubMed  Google Scholar 

  80. Ishiguro H, Koga M, Horiuchi Y, Inada T, Iwata N, Ozaki N, Ujike H, Muratake T, Someya T, Arinami T (2007) PICK1 is not a susceptibility gene for schizophrenia in a Japanese population: association study in a large case-control population. Neurosci Res 58:145–148

    Article  CAS  PubMed  Google Scholar 

  81. Alfonso S, Kessels HW, Banos CC, Chan TR, Lin ET, Kumaravel G, Scannevin RH, Rhodes KJ, Huganir R, Guckian KM, Dunah AW, Malinow R (2014) Synapto-depressive effects of amyloid beta require PICK1. Eur J Neurosci 39:1225–1233

    Article  PubMed  PubMed Central  Google Scholar 

  82. He J, Xia M, Yeung PKK, Li J, Li Z, Chung KK, Chung SK, Xia J (2018) PICK1 inhibits the E3 ubiquitin ligase activity of Parkin and reduces its neuronal protective effect. Proc Natl Acad Sci USA 115:E7193–E7201

    Article  CAS  PubMed  Google Scholar 

  83. Bertaso F, Zhang C, Scheschonka A, de Bock F, Fontanaud P, Marin P, Huganir RL, Betz H, Bockaert J, Fagni L, Lerner-Natoli M (2008) PICK1 uncoupling from mGluR7a causes absence-like seizures. Nat Neurosci 11:940–948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Focant MC, Goursaud S, Boucherie C, Dumont AO, Hermans E (2013) PICK1 expression in reactive astrocytes within the spinal cord of amyotrophic lateral sclerosis (ALS) rats. Neuropathol Appl Neurobiol 39:231–242

    Article  CAS  PubMed  Google Scholar 

  85. Cao M, Mao Z, Kam C, Xiao N, Cao X, Shen C, Cheng KK, Xu A, Lee KM, Jiang L, Xia J (2013) PICK1 and ICA69 control insulin granule trafficking and their deficiencies lead to impaired glucose tolerance. PLoS Biol 11:e1001541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Qian M, Lou Y, Wang Y, Zhang M, Jiang Q, Mo Y, Han K, Jin S, Dai Q, Yu Y, Wang Z, Wang J (2018) PICK1 deficiency exacerbates sepsis-associated acute lung injury and impairs glutathione synthesis via reduction of xCT. Free Radic Biol Med 118:23–34

    Article  CAS  PubMed  Google Scholar 

  87. Lin EYS, Silvian LF, Marcotte DJ, Banos CC, Jow F, Chan TR, Arduini RM, Qian F, Baker DP, Bergeron C, Hession CA, Huganir RL, Borenstein CF, Enyedy I, Zou J, Rohde E, Wittmann M, Kumaravel G, Rhodes KJ, Scannevin RH, Dunah AW, Guckian KM (2018) Potent PDZ-domain PICK1 inhibitors that modulate amyloid beta-mediated synaptic dysfunction. Sci Rep 8:13438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Thorsen TS, Madsen KL, Rebola N, Rathje M, Anggono V, Bach A, Moreira IS, Stuhr-Hansen N, Dyhring T, Peters D, Beuming T, Huganir R, Weinstein H, Mulle C, Stromgaard K, Ronn LC, Gether U (2010) Identification of a small-molecule inhibitor of the PICK1 PDZ domain that inhibits hippocampal LTP and LTD. Proc Natl Acad Sci USA 107:413–418

    Article  PubMed  Google Scholar 

  89. Gautreau A, Vacher S, Sousa-Blin C, Derivery E, Gorelik R (2014) Use of arpin a new inhibitor of the Arp2/3 complex for the diagnosis and treatment of diseases. Patent# US20160199445A1

  90. Dang I, Gorelik R, Sousa-Blin C, Derivery E, Guerin C, Linkner J, Nemethova M, Dumortier JG, Giger FA, Chipysheva TA, Ermilova VD, Vacher S, Campanacci V, Herrada I, Planson AG, Fetics S, Henriot V, David V, Oguievetskaia K, Lakisic G, Pierre F, Steffen A, Boyreau A, Peyrieras N, Rottner K, Zinn-Justin S, Cherfils J, Bieche I, Alexandrova AY, David NB, Small JV, Faix J, Blanchoin L, Gautreau A (2013) Inhibitory signalling to the Arp2/3 complex steers cell migration. Nature 503:281–284

    Article  CAS  PubMed  Google Scholar 

  91. Fetics S, Thureau A, Campanacci V, Aumont-Nicaise M, Dang I, Gautreau A, Perez J, Cherfils J (2016) Hybrid structural analysis of the Arp2/3 regulator arpin identifies its acidic tail as a primary binding epitope. Structure 24:252–260

    Article  CAS  PubMed  Google Scholar 

  92. Sokolova OS, Chemeris A, Guo S, Alioto SL, Gandhi M, Padrick S, Pechnikova E, David V, Gautreau A, Goode BL (2017) Structural basis of Arp2/3 complex inhibition by GMF, Coronin, and Arpin. J Mol Biol 429:237–248

    Article  CAS  PubMed  Google Scholar 

  93. Jia D, Gomez TS, Metlagel Z, Umetani J, Otwinowski Z, Rosen MK, Billadeau DD (2010) WASH and WAVE actin regulators of the Wiskott–Aldrich syndrome protein (WASP) family are controlled by analogous structurally related complexes. Proc Natl Acad Sci USA 107:10442–10447

    Article  PubMed  Google Scholar 

  94. Maiuri P, Rupprecht JF, Wieser S, Ruprecht V, Benichou O, Carpi N, Coppey M, De Beco S, Gov N, Heisenberg CP, Lage Crespo C, Lautenschlaeger F, Le Berre M, Lennon-Dumenil AM, Raab M, Thiam HR, Piel M, Sixt M, Voituriez R (2015) Actin flows mediate a universal coupling between cell speed and cell persistence. Cell 161:374–386

    Article  CAS  PubMed  Google Scholar 

  95. Gorelik R, Gautreau A (2015) The Arp2/3 inhibitory protein arpin induces cell turning by pausing cell migration. Cytoskeleton (Hoboken) 72:362–371

    Article  CAS  Google Scholar 

  96. Dang I, Linkner J, Yan J, Irimia D, Faix J, Gautreau A (2017) The Arp2/3 inhibitory protein Arpin is dispensable for chemotaxis. Biol Cell 109:162–166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Wu C, Asokan SB, Berginski ME, Haynes EM, Sharpless NE, Griffith JD, Gomez SM, Bear JE (2012) Arp2/3 is critical for lamellipodia and response to extracellular matrix cues but is dispensable for chemotaxis. Cell 148:973–987

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Wu C, Haynes EM, Asokan SB, Simon JM, Sharpless NE, Baldwin AS, Davis IJ, Johnson GL, Bear JE (2013) Loss of Arp2/3 induces an NF-kappaB-dependent, nonautonomous effect on chemotactic signaling. J Cell Biol 203:907–916

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Krause M, Gautreau A (2014) Steering cell migration: lamellipodium dynamics and the regulation of directional persistence. Nat Rev Mol Cell Biol 15:577–590

    Article  CAS  PubMed  Google Scholar 

  100. Deng WS, Zhang J, Ju H, Zheng HM, Wang J, Wang S, Zhang DL (2015) Arpin contributes to bacterial translocation and development of severe acute pancreatitis. World J Gastroenterol 21:4293–4301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Liu X, Zhao B, Wang H, Wang Y, Niu M, Sun M, Zhao Y, Yao R, Qu Z (2016) Aberrant expression of Arpin in human breast cancer and its clinical significance. J Cell Mol Med 20:450–458

    Article  CAS  PubMed  Google Scholar 

  102. Lomakina ME, Lallemand F, Vacher S, Molinie N, Dang I, Cacheux W, Chipysheva TA, Ermilova VD, de Koning L, Dubois T, Bieche I, Alexandrova AY, Gautreau A (2016) Arpin downregulation in breast cancer is associated with poor prognosis. Br J Cancer 114:545–553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Li Y, Qiu J, Pang T, Guo Z, Su Y, Zeng Q, Zhang X (2017) Restoration of Arpin suppresses aggressive phenotype of breast cancer cells. Biomed Pharmacother 92:116–121

    Article  CAS  PubMed  Google Scholar 

  104. Molinie N, Rubtsova SN, Fokin A, Visweshwaran SP, Rocques N, Polesskaya A, Schnitzler A, Vacher S, Denisov EV, Tashireva LA, Perelmuter VM, Cherdyntseva NV, Bieche I, Gautreau AM (2019) Cortical branched actin determines cell cycle progression. Cell Res. https://doi.org/10.1038/s41422-019-0168-1

    Article  PubMed  Google Scholar 

  105. Li T, Zheng HM, Deng NM, Jiang YJ, Wang J, Zhang DL (2017) Clinicopathological and prognostic significance of aberrant Arpin expression in gastric cancer. World J Gastroenterol 23:1450–1457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Zhang SR, Li H, Wang WQ, Jin W, Xu JZ, Xu HX, Wu CT, Gao HL, Li S, Li TJ, Zhang WH, Xu SS, Ni QX, Yu XJ, Liu L (2018) Arpin downregulation is associated with poor prognosis in pancreatic ductal adenocarcinoma. Eur J Surg Oncol 45:769–775

    Article  PubMed  Google Scholar 

  107. Sundaram GM, Ismail HM, Bashir M, Muhuri M, Vaz C, Nama S, Ow GS, Vladimirovna IA, Ramalingam R, Burke B, Tanavde V, Kuznetsov V, Lane EB, Sampath P (2017) EGF hijacks miR-198/FSTL1 wound-healing switch and steers a two-pronged pathway toward metastasis. J Exp Med 214:2889–2900

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Franzen O, Ermel R, Sukhavasi K, Jain R, Jain A, Betsholtz C, Giannarelli C, Kovacic JC, Ruusalepp A, Skogsberg J, Hao K, Schadt EE, Bjorkegren JLM (2018) Global analysis of A-to-I RNA editing reveals association with common disease variants. PeerJ 6:e4466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Nolen BJ, Tomasevic N, Russell A, Pierce DW, Jia Z, McCormick CD, Hartman J, Sakowicz R, Pollard TD (2009) Characterization of two classes of small molecule inhibitors of Arp2/3 complex. Nature 460:1031–1034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Hetrick B, Han MS, Helgeson LA, Nolen BJ (2013) Small molecules CK-666 and CK-869 inhibit actin-related protein 2/3 complex by blocking an activating conformational change. Chem Biol 20:701–712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Henson JH, Yeterian M, Weeks RM, Medrano AE, Brown BL, Geist HL, Pais MD, Oldenbourg R, Shuster CB (2015) Arp2/3 complex inhibition radically alters lamellipodial actin architecture, suspended cell shape, and the cell spreading process. Mol Biol Cell 26:887–900

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Ilatovskaya DV, Chubinskiy-Nadezhdin V, Pavlov TS, Shuyskiy LS, Tomilin V, Palygin O, Staruschenko A, Negulyaev YA (2013) Arp2/3 complex inhibitors adversely affect actin cytoskeleton remodeling in the cultured murine kidney collecting duct M-1 cells. Cell Tissue Res 354:783–792

    Article  CAS  PubMed  Google Scholar 

  113. Wilson K, Lewalle A, Fritzsche M, Thorogate R, Duke T, Charras G (2013) Mechanisms of leading edge protrusion in interstitial migration. Nat Commun 4:2896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Yang Q, Zhang XF, Pollard TD, Forscher P (2012) Arp2/3 complex-dependent actin networks constrain myosin II function in driving retrograde actin flow. J Cell Biol 197:939–956

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Li J, Wang Z, Chu Q, Jiang K, Li J, Tang N (2018) The strength of mechanical forces determines the differentiation of alveolar epithelial cells. Dev Cell 44(297–312):e5

    Google Scholar 

  116. Harris AR, Daeden A, Charras GT (2014) Formation of adherens junctions leads to the emergence of a tissue-level tension in epithelial monolayers. J Cell Sci 127:2507–2517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Van Itallie CM, Tietgens AJ, Krystofiak E, Kachar B, Anderson JM (2015) A complex of ZO-1 and the BAR-domain protein TOCA-1 regulates actin assembly at the tight junction. Mol Biol Cell 26:2769–2787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Abu Taha A, Taha M, Seebach J, Schnittler HJ (2014) ARP2/3-mediated junction-associated lamellipodia control VE-cadherin-based cell junction dynamics and maintain monolayer integrity. Mol Biol Cell 25:245–256

    Article  PubMed  Google Scholar 

  119. Efimova N, Svitkina TM (2018) Branched actin networks push against each other at adherens junctions to maintain cell–cell adhesion. J Cell Biol 217:1827–1845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Belvitch P, Brown ME, Brinley BN, Letsiou E, Rizzo AN, Garcia JGN, Dudek SM (2017) The ARP 2/3 complex mediates endothelial barrier function and recovery. Pulm Circ 7:200–210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Goley ED, Rammohan A, Znameroski EA, Firat-Karalar EN, Sept D, Welch MD (2010) An actin-filament-binding interface on the Arp2/3 complex is critical for nucleation and branch stability. Proc Natl Acad Sci USA 107:8159–8164

    Article  PubMed  Google Scholar 

  122. Sumida GM, Yamada S (2015) Rho GTPases and the downstream effectors actin-related protein 2/3 (Arp2/3) complex and myosin II induce membrane fusion at self-contacts. J Biol Chem 290:3238–3247

    Article  CAS  PubMed  Google Scholar 

  123. Sun SC, Wang ZB, Xu YN, Lee SE, Cui XS, Kim NH (2011) Arp2/3 complex regulates asymmetric division and cytokinesis in mouse oocytes. PLoS One 6:e18392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Zhou K, Muroyama A, Underwood J, Leylek R, Ray S, Soderling SH, Lechler T (2013) Actin-related protein2/3 complex regulates tight junctions and terminal differentiation to promote epidermal barrier formation. Proc Natl Acad Sci USA 110:E3820–E3829

    Article  PubMed  Google Scholar 

  125. Zhou T, Wang CH, Yan H, Zhang R, Zhao JB, Qian CF, Xiao H, Liu HY (2016) Inhibition of the Rac1-WAVE2-Arp2/3 signaling pathway promotes radiosensitivity via downregulation of cofilin-1 in U251 human glioma cells. Mol Med Rep 13:4414–4420

    Article  CAS  PubMed  Google Scholar 

  126. Wang F, An GY, Zhang Y, Liu HL, Cui XS, Kim NH, Sun SC (2014) Arp2/3 complex inhibition prevents meiotic maturation in porcine oocytes. PLoS One 9:e87700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Velle KB, Campellone KG (2017) Extracellular motility and cell-to-cell transmission of enterohemorrhagic E. coli is driven by EspFU-mediated actin assembly. PLoS Pathog 13:e1006501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Miller HE, Larson CL, Heinzen RA (2018) Actin polymerization in the endosomal pathway, but not on the Coxiella-containing vacuole, is essential for pathogen growth. PLoS Pathog 14:e1007005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Burke TA, Christensen JR, Barone E, Suarez C, Sirotkin V, Kovar DR (2014) Homeostatic actin cytoskeleton networks are regulated by assembly factor competition for monomers. Curr Biol 24:579–585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Sen B, Uzer G, Samsonraj RM, Xie Z, McGrath C, Styner M, Dudakovic A, van Wijnen AJ, Rubin J (2017) Intranuclear actin structure modulates mesenchymal stem cell differentiation. Stem Cells 35:1624–1635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Beckham Y, Vasquez RJ, Stricker J, Sayegh K, Campillo C, Gardel ML (2014) Arp2/3 inhibition induces amoeboid-like protrusions in MCF10A epithelial cells by reduced cytoskeletal-membrane coupling and focal adhesion assembly. PLoS One 9:e100943

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Yamagishi Y, Oya K, Matsuura A, Abe H (2018) Use of CK-548 and CK-869 as Arp2/3 complex inhibitors directly suppresses microtubule assembly both in vitro and in vivo. Biochem Biophys Res Commun 496:834–839

    Article  CAS  PubMed  Google Scholar 

  133. Mizuno K (2013) Signaling mechanisms and functional roles of cofilin phosphorylation and dephosphorylation. Cell Signal 25:457–469

    Article  CAS  PubMed  Google Scholar 

  134. Hsiao JY, Goins LM, Petek NA, Mullins RD (2015) Arp2/3 complex and cofilin modulate binding of tropomyosin to branched actin networks. Curr Biol 25:1573–1582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Shaw AE, Bamburg JR (2017) Peptide regulation of cofilin activity in the CNS: a novel therapeutic approach for treatment of multiple neurological disorders. Pharmacol Ther 175:17–27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Work in the laboratory of Michael Schnoor regarding Arp2/3 inhibition is funded by Grant 284292 of the Mexican National Council for Science and Technology (Conacyt).

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  1. Department for Molecular Biomedicine, CINVESTAV-IPN, Av. IPN 2508, San Pedro Zacatenco, GAM, 07360, Mexico City, Mexico

    Sandra Chánez-Paredes, Armando Montoya-García & Michael Schnoor

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  1. Sandra Chánez-Paredes
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Chánez-Paredes, S., Montoya-García, A. & Schnoor, M. Cellular and pathophysiological consequences of Arp2/3 complex inhibition: role of inhibitory proteins and pharmacological compounds. Cell. Mol. Life Sci. 76, 3349–3361 (2019). https://doi.org/10.1007/s00018-019-03128-y

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  • DOI: https://doi.org/10.1007/s00018-019-03128-y

Keywords

  • Actin cytoskeleton
  • Adhesion
  • Migration
  • Cortactin
  • Vesicle trafficking
  • Endosome
  • Cofilin
  • CK666