Actin reorganization is a tightly regulated process that co-ordinates complex cellular events, such as cell migration, chemotaxis, phagocytosis and adhesion, but the molecular mechanisms that underlie these processes are not well understood. SCAR (suppressor of cAMP receptor)/WAVE [WASP (Wiskott-Aldrich syndrome protein)-family verprolin homology protein] proteins are members of the conserved WASP family of cytoskeletal regulators, which play a critical role in actin dynamics by triggering Arp2/3 (actin-related protein 2/3)-dependent actin nucleation. SCAR/WAVEs are thought to be regulated by a pentameric complex which also contains Abi (Abl-interactor), Nap (Nck-associated protein), PIR121 (p53-inducible mRNA 121) and HSPC300 (haematopoietic stem progenitor cell 300), but the structural organization of the complex and the contribution of its individual components to the regulation of SCAR/WAVE function remain unclear. Additional features of SCAR/WAVE regulation are highlighted by the discovery of other interactors and distinct complexes. It is likely that the combinatorial assembly of different components of SCAR/WAVE complexes will prove to be vital for their roles at the centre of dynamic actin reorganization.
"During this process, the external chemotactic gradient is amplied within the cell resulting in a steeper intracellular concentration gradient than is provided by the external chemotactic gradient . The accumulation of PIP3 at the membrane recruits actin polymerization enhancing proteins  such as the actin crosslinker Arp2/3  or the actin capping protein Coronin  to the site of stimulation, thus initiating the formation of a new pseudopod. At the rear of the cell, PTEN perturbs PIP3 accumulation, preventing lateral pseudopods . "
"An increasing knowledge of actin polymerization regulation is starting to provide a general, more qualitative picture of how biochemical processes control cell migration. Unlike mammalian cells lacking the SCAR protein, Dictyostelium cells lacking SCAR (scrA − cells) can still move, albeit with reduced chemoattractant-induced F-actin polymerization, presumably by employing other F-actin nucleation–promoting factors such as WASP (Blagg et al., 2003; Ibarra and Insall, 2005). On the other hand, Dictyostelium cells lacking the SCAR/WAVE complex protein PIR121 (pirA − cells) undergo increased F-actin polymerization, enhanced pseudopod activity, and reduced substrate adhesion (Blagg et al., 2003). "
[Show abstract][Hide abstract] ABSTRACT: Cell migration requires a tightly regulated, spatiotemporal coordination of underlying biochemical pathways. Crucial to cell migration is SCAR/WAVE-mediated dendritic F-actin polymerization at the cell's leading edge. Our goal is to understand the role the SCAR/WAVE complex plays in the mechanics of amoeboid migration. To this aim, we measured and compared the traction stresses exerted by Dictyostelium cells lacking the SCAR/WAVE complex proteins PIR121 (pirA(-)) and SCAR (scrA(-)) with those of wild-type cells while they were migrating on flat, elastic substrates. We found that, compared to wild type, both mutant strains exert traction stresses of different strengths that correlate with their F-actin levels. In agreement with previous studies, we found that wild-type cells migrate by repeating a motility cycle in which the cell length and strain energy exerted by the cells on their substrate vary periodically. Our analysis also revealed that scrA(-) cells display an altered motility cycle with a longer period and a lower migration velocity, whereas pirA(-) cells migrate in a random manner without implementing a periodic cycle. We present detailed characterization of the traction-stress phenotypes of the various cell lines, providing new insights into the role of F-actin polymerization in regulating cell-substratum interactions and stresses required for motility.
Molecular biology of the cell 09/2011; 22(21):3995-4003. DOI:10.1091/mbc.E11-03-0278 · 4.47 Impact Factor
"WASH, like SCAR/WAVEs (Ibarra et al., 2005), is regulated as part of a protein complex (Gomez and Billadeau, 2009). As with SCAR/WAVE and its regulatory complex, there are few clues about its function from protein sequences; despite >200 kD of protein, there are no known domains outside the Arp2/3-and actin-binding WASH C terminus. "
[Show abstract][Hide abstract] ABSTRACT: WASP and SCAR homologue (WASH) is a recently identified and evolutionarily conserved regulator of actin polymerization. In this paper, we show that WASH coats mature Dictyostelium discoideum lysosomes and is essential for exocytosis of indigestible material. A related process, the expulsion of the lethal endosomal pathogen Cryptococcus neoformans from mammalian macrophages, also uses WASH-coated vesicles, and cells expressing dominant negative WASH mutants inefficiently expel C. neoformans. D. discoideum WASH causes filamentous actin (F-actin) patches to form on lysosomes, leading to the removal of vacuolar adenosine triphosphatase (V-ATPase) and the neutralization of lysosomes to form postlysosomes. Without WASH, no patches or coats are formed, neutral postlysosomes are not seen, and indigestible material such as dextran is not exocytosed. Similar results occur when actin polymerization is blocked with latrunculin. V-ATPases are known to bind avidly to F-actin. Our data imply a new mechanism, actin-mediated sorting, in which WASH and the Arp2/3 complex polymerize actin on vesicles to drive the separation and recycling of proteins such as the V-ATPase.
The Journal of Cell Biology 05/2011; 193(5):831-9. DOI:10.1083/jcb.201009119 · 9.83 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.