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Gene Review

ACTR2  -  ARP2 actin-related protein 2 homolog (yeast)

Homo sapiens

Synonyms: ARP2, Actin-like protein 2, Actin-related protein 2
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Disease relevance of ACTR2

  • Actin rings are vital for osteoclastic bone resorption, and actin-related protein 2/3 complex is a pivotal regulator of actin polymerization [1].
  • The bacteria Listeria and Shigella bypass the signalling pathway and harness the Arp2/3 complex to induce actin assembly and to propel themselves in living cells [2].
  • Neural Wiskott-Aldrich syndrome protein (N-WASP) functions in several intracellular events including filopodium formation, vesicle transport and movement of Shigella frexneri and vaccinia virus, by stimulating rapid actin polymerization through the Arp2/3 complex [3].
  • Inhibiting the Arp2/3 complex limits infection of both intracellular mature vaccinia virus and primate lentiviruses [4].
  • Constitutive inhibition of the Arp2/3 complex in the T-cell line H9 also blocked replication of HIV-1 [4].

High impact information on ACTR2

  • Microorganisms either activate Arp2/3 complex directly or usurp N-WASP to initiate actin polymerization [5].
  • Regulation of actin filament network formation through ARP2/3 complex: activation by a diverse array of proteins [5].
  • In particular, 1) the structure of actin was resolved from crystals in the absence of cocrystallized actin binding proteins (ABPs), 2) the prokaryotic ancestral gene of actin was crystallized and its function as a bacterial cytoskeleton was revealed, and 3) the structure of the Arp2/3 complex was described for the first time [6].
  • The Wiskott-Aldrich syndrome protein (WASP; encoded by the gene WAS) and its homologs are important regulators of the actin cytoskeleton, mediating communication between Rho-family GTPases and the actin nucleation/crosslinking factor, the Arp2/3 complex [7].
  • Direct observation of dendritic actin filament networks nucleated by Arp2/3 complex and WASP/Scar proteins [8].

Chemical compound and disease context of ACTR2


Biological context of ACTR2

  • Point mutations in this conserved sequence motif suggest that it forms an amphipathic helix that is required in biochemical assays for activation of Arp2/3 complex [10].
  • Therefore, by binding both CD2AP and the Arp2/3 complex, cortactin links receptor endocytosis to actin polymerization, which may facilitate the trafficking of internalized growth factor receptors [11].
  • In addition, cortactin-deficient cells have increased lamellipod dynamics but show reduced net translocation, suggesting that cortactin can contribute to cell polarity by controlling the extent of Arp2/3 activation by WASP family members and the stability of the F-actin network [12].
  • We have mapped the binding site for the Arp2/3 complex to the hinge region of vinculin, and a point mutation in this region selectively blocks binding to the Arp2/3 complex [13].
  • Platelet activation by alpha-thrombin, but not saturating concentrations of fibrillar collagen or adenosine 5'-diphosphate, uniquely assemble an IQGAP2/arp2/3-actin cytoplasmic complex, an association regulated by guanosine triphosphate rac1 ([GTP]rac1) but not by [GTP]cdc42 [14].

Anatomical context of ACTR2


Associations of ACTR2 with chemical compounds

  • Arp2/3 complex redistributes to the edge of the lamellae and to the Triton X-100-insoluble actin cytoskeleton of activated WASp-deficient platelets [17].
  • These results suggest that Grb2 may activate Arp2/3 complex-mediated actin polymerization downstream from the receptor tyrosine kinase signaling pathway [18].
  • The recruitment of the Arp2/3 complex to vinculin may be one mechanism through which actin polymerization and membrane protrusion are coupled to integrin-mediated adhesion [13].
  • Phosphatidylinositol 4,5 bisphosphate (PIP(2)) micelles allowed WASp to activate actin nucleation by Arp2/3 complex, and this was further enhanced twofold by GTP-Cdc42 [16].
  • Intact and Fab fragments of alpha Arp2 inhibited TRAP-stimulated actin-polymerizing activity in platelet extracts as measured by the pyrene assay [19].

Physical interactions of ACTR2

  • Here we show by differential line broadening in NMR spectra that the C (central) and A (acidic) segments of VCA domains from WASP, N-WASP and Scar bind Arp2/3 complex [10].
  • WASp WA binds both the Arp2/3 complex and actin monomers, but the mechanism by which it activates the Arp2/3 complex is not known [20].
  • We propose that ActA and endogenous WASP family proteins promote Arp2/3-dependent nucleation by similar mechanisms and require simultaneous binding of Arp2 and Arp3 [21].
  • Involvement of Arp2/3 complex in MCP-1-induced chemotaxis [22].
  • Cortactin also binds the Arp2/3 complex via an A domain; however, it also binds to actin filaments, which helps activate the Arp2/3 complex and stabilise the newly created branches between the filaments [23].

Regulatory relationships of ACTR2


Other interactions of ACTR2

  • Integration of multiple signals through cooperative regulation of the N-WASP-Arp2/3 complex [28].
  • Wiskott-Aldrich-syndrome mutations in the WA domain that alter nucleation by the Arp2/3 complex over a tenfold range without affecting affinity for actin or the Arp2/3 complex indicate that there may be an activation step in the nucleation pathway [24].
  • Interaction of WASP/Scar proteins with actin and vertebrate Arp2/3 complex [24].
  • RESULTS: A 3-fold increase in Arp2 and Arp3 was detected during RANKL-induced differentiation of RAW 264.7 cells into osteoclast-like cells [1].
  • These data suggest that the HS1 coiled-coil region acts synergistically with the repeat domain in the modulation of the Arp2/3 complex-mediated actin polymerization [25].

Analytical, diagnostic and therapeutic context of ACTR2


  1. Actin-related protein 2/3 complex is required for actin ring formation. Hurst, I.R., Zuo, J., Jiang, J., Holliday, L.S. J. Bone Miner. Res. (2004) [Pubmed]
  2. Reconstitution of actin-based motility of Listeria and Shigella using pure proteins. Loisel, T.P., Boujemaa, R., Pantaloni, D., Carlier, M.F. Nature (1999) [Pubmed]
  3. IRSp53 is an essential intermediate between Rac and WAVE in the regulation of membrane ruffling. Miki, H., Yamaguchi, H., Suetsugu, S., Takenawa, T. Nature (2000) [Pubmed]
  4. Inhibiting the Arp2/3 complex limits infection of both intracellular mature vaccinia virus and primate lentiviruses. Komano, J., Miyauchi, K., Matsuda, Z., Yamamoto, N. Mol. Biol. Cell (2004) [Pubmed]
  5. Regulation of actin filament network formation through ARP2/3 complex: activation by a diverse array of proteins. Higgs, H.N., Pollard, T.D. Annu. Rev. Biochem. (2001) [Pubmed]
  6. Actin binding proteins: regulation of cytoskeletal microfilaments. dos Remedios, C.G., Chhabra, D., Kekic, M., Dedova, I.V., Tsubakihara, M., Berry, D.A., Nosworthy, N.J. Physiol. Rev. (2003) [Pubmed]
  7. Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia. Devriendt, K., Kim, A.S., Mathijs, G., Frints, S.G., Schwartz, M., Van Den Oord, J.J., Verhoef, G.E., Boogaerts, M.A., Fryns, J.P., You, D., Rosen, M.K., Vandenberghe, P. Nat. Genet. (2001) [Pubmed]
  8. Direct observation of dendritic actin filament networks nucleated by Arp2/3 complex and WASP/Scar proteins. Blanchoin, L., Amann, K.J., Higgs, H.N., Marchand, J.B., Kaiser, D.A., Pollard, T.D. Nature (2000) [Pubmed]
  9. Cortactin overexpression regulates actin-related protein 2/3 complex activity, motility, and invasion in carcinomas with chromosome 11q13 amplification. Rothschild, B.L., Shim, A.H., Ammer, A.G., Kelley, L.C., Irby, K.B., Head, J.A., Chen, L., Varella-Garcia, M., Sacks, P.G., Frederick, B., Raben, D., Weed, S.A. Cancer Res. (2006) [Pubmed]
  10. A conserved amphipathic helix in WASP/Scar proteins is essential for activation of Arp2/3 complex. Panchal, S.C., Kaiser, D.A., Torres, E., Pollard, T.D., Rosen, M.K. Nat. Struct. Biol. (2003) [Pubmed]
  11. A Cortactin-CD2-associated protein (CD2AP) complex provides a novel link between epidermal growth factor receptor endocytosis and the actin cytoskeleton. Lynch, D.K., Winata, S.C., Lyons, R.J., Hughes, W.E., Lehrbach, G.M., Wasinger, V., Corthals, G., Cordwell, S., Daly, R.J. J. Biol. Chem. (2003) [Pubmed]
  12. A neural Wiskott-Aldrich Syndrome protein-mediated pathway for localized activation of actin polymerization that is regulated by cortactin. Kempiak, S.J., Yamaguchi, H., Sarmiento, C., Sidani, M., Ghosh, M., Eddy, R.J., Desmarais, V., Way, M., Condeelis, J., Segall, J.E. J. Biol. Chem. (2005) [Pubmed]
  13. Recruitment of the Arp2/3 complex to vinculin: coupling membrane protrusion to matrix adhesion. DeMali, K.A., Barlow, C.A., Burridge, K. J. Cell Biol. (2002) [Pubmed]
  14. IQGAP2 functions as a GTP-dependent effector protein in thrombin-induced platelet cytoskeletal reorganization. Schmidt, V.A., Scudder, L., Devoe, C.E., Bernards, A., Cupit, L.D., Bahou, W.F. Blood (2003) [Pubmed]
  15. WAVE/Scars in platelets. Oda, A., Miki, H., Wada, I., Yamaguchi, H., Yamazaki, D., Suetsugu, S., Nakajima, M., Nakayama, A., Okawa, K., Miyazaki, H., Matsuno, K., Ochs, H.D., Machesky, L.M., Fujita, H., Takenawa, T. Blood (2005) [Pubmed]
  16. Activation by Cdc42 and PIP(2) of Wiskott-Aldrich syndrome protein (WASp) stimulates actin nucleation by Arp2/3 complex. Higgs, H.N., Pollard, T.D. J. Cell Biol. (2000) [Pubmed]
  17. Normal Arp2/3 complex activation in platelets lacking WASp. Falet, H., Hoffmeister, K.M., Neujahr, R., Hartwig, J.H. Blood (2002) [Pubmed]
  18. GRB2 links signaling to actin assembly by enhancing interaction of neural Wiskott-Aldrich syndrome protein (N-WASp) with actin-related protein (ARP2/3) complex. Carlier, M.F., Nioche, P., Broutin-L'Hermite, I., Boujemaa, R., Le Clainche, C., Egile, C., Garbay, C., Ducruix, A., Sansonetti, P., Pantaloni, D. J. Biol. Chem. (2000) [Pubmed]
  19. Arp2/3 complex is required for actin polymerization during platelet shape change. Li, Z., Kim, E.S., Bearer, E.L. Blood (2002) [Pubmed]
  20. Influence of the C terminus of Wiskott-Aldrich syndrome protein (WASp) and the Arp2/3 complex on actin polymerization. Higgs, H.N., Blanchoin, L., Pollard, T.D. Biochemistry (1999) [Pubmed]
  21. Activation of the Arp2/3 complex by the Listeria acta protein. Acta binds two actin monomers and three subunits of the Arp2/3 complex. Zalevsky, J., Grigorova, I., Mullins, R.D. J. Biol. Chem. (2001) [Pubmed]
  22. Involvement of Arp2/3 complex in MCP-1-induced chemotaxis. Mukai, Y., Iwaya, K., Ogawa, H., Mukai, K. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  23. Integration of signals to the Arp2/3 complex. Weaver, A.M., Young, M.E., Lee, W.L., Cooper, J.A. Curr. Opin. Cell Biol. (2003) [Pubmed]
  24. Interaction of WASP/Scar proteins with actin and vertebrate Arp2/3 complex. Marchand, J.B., Kaiser, D.A., Pollard, T.D., Higgs, H.N. Nat. Cell Biol. (2001) [Pubmed]
  25. The coiled-coil domain is required for HS1 to bind to F-actin and activate Arp2/3 complex. Hao, J.J., Zhu, J., Zhou, K., Smith, N., Zhan, X. J. Biol. Chem. (2005) [Pubmed]
  26. Grb2 and Nck act cooperatively to promote actin-based motility of vaccinia virus. Scaplehorn, N., Holmström, A., Moreau, V., Frischknecht, F., Reckmann, I., Way, M. Curr. Biol. (2002) [Pubmed]
  27. Interaction of cortactin and Arp2/3 complex is required for sphingosine-1-phosphate-induced endothelial cell remodeling. Li, Y., Uruno, T., Haudenschild, C., Dudek, S.M., Garcia, J.G., Zhan, X. Exp. Cell Res. (2004) [Pubmed]
  28. Integration of multiple signals through cooperative regulation of the N-WASP-Arp2/3 complex. Prehoda, K.E., Scott, J.A., Mullins, R.D., Lim, W.A. Science (2000) [Pubmed]
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