Gene name - SCAR
Cytological map position - 32C1-4
Function - signaling
Symbol - SCAR
FlyBase ID: FBgn0041781
Genetic map position - 2L
Classification - WASp family
Cellular location - cytoplasmic
The Arp2/3 complex (see Drosophila Arp2/3 component Suppressor of profilin 2) and its activators, Scar/WAVE and Wiskott-Aldrich Syndrome protein (WASp), promote actin polymerization in vitro and have been proposed to influence cell shape and motility in vivo. The Drosophila Scar homologue, SCAR, localizes to actin-rich structures and is required for normal cell morphology in multiple cell types throughout development. In particular, SCAR function is essential for cytoplasmic organization in the blastoderm, axon development in the central nervous system, egg chamber structure during oogenesis, and adult eye morphology. Highly similar developmental requirements are found for subunits of the Arp2/3 complex. In the blastoderm, SCAR and Arp2/3 mutations result in a reduction in the amount of cortical filamentous actin and the disruption of dynamically regulated actin structures. Remarkably, the single Drosophila WASp homologue, Wasp, is largely dispensable for these numerous Arp2/3-dependent functions, whereas SCAR does not contribute to cell fate decisions in which Wasp and Arp2/3 play an essential role. Thus SCAR is a major component of Arp2/3-dependent cell morphology during Drosophila development and demonstrates that the Arp2/3 complex can govern distinct cell biological events in response to SCAR and Wasp regulation (Zallen, 2002).
Biochemical studies have provided detailed information about the molecules that influence actin dynamics. Of particular significance is the Arp2/3 complex that stimulates microfilament nucleation, the rate-limiting step in actin polymerization. The Arp2/3 complex consists of seven protein subunits, including the actin-related Arp2 and Arp3, and is conserved among eukaryotes. Members of the evolutionarily conserved Wiskott-Aldrich Syndrome protein and Scar/WAVE family function as strong potentiators of Arp2/3 complex activity. Distinct WASp and Scar/WAVE branches of this family have been recognized in diverse organisms, including Dictyostelium, Caenorhabditis elegans, Drosophila, and mammals. WASp and Scar/WAVE proteins share a common domain structure that mediates activation of the Arp2/3 complex in response to multiple signaling pathways. All members of the WASp-Scar/WAVE family possess a common COOH-terminal (WA) domain that stimulates actin polymerization through association with monomeric actin and the Arp2/3 complex, whereas their NH2-terminal domains are structurally distinct and serve as signal-responsive regulatory regions. The molecular mechanisms controlling WASp function are well characterized, whereas regulatory aspects of Scar function are only now beginning to emerge (Takenawa, 2001; Zallen, 2002 and references therein).
The single WASp/Scar protein in budding yeast is required for processes that have been shown to be Arp2/3 dependent (Li, 1997; Naqvi, 1998), indicating a functional connection in vivo as well as in vitro. In what cellular contexts does this system operate during development of multicellular organisms? Are the distinct WASp and Scar homologs present in such organisms involved in common or separate Arp2/3-dependent processes? The first mutant alleles of the single Drosophila Scar/WAVE homolog, SCAR, have now been studied and SCAR functions have been compared to those Drosophila of WASp (Ben-Yaacov, 2001). SCAR and WASp appear to represent the only homologs of their respective subfamilies in the Drosophila genome, providing an opportunity to compare the functional requirements for these two major branches of the WASp/Scar protein family. Furthermore, the in vivo relevance of WASp and Scar to the Arp2/3 complex functions, which occur during development of a multicellular organism, can be assessed using mutant alleles in components of the Drosophila Arp2/3 complex. The results suggest that WASp and SCAR mediate distinct subsets of Arp2/3-dependent processes during Drosophila development. Although WASp is required specifically for proper execution of asymmetric cell divisions in neural lineages, SCAR plays a major role in the Arp2/3 complex-dependent regulation of cell morphology (Zallen, 2002).
Highly similar requirements for Drosophila SCAR and Arp2/3 complex components in regulating cytoplasmic organization in the blastoderm and cell morphology in CNS neurons, egg chambers, and adult eyes are demonstrated. These results suggest that SCAR and Arp2/3 complex components function in a common pathway in vivo, consistent with their well-established regulatory interaction in vitro. These roles of SCAR and the Arp2/3 complex are largely independent of WASp function, suggesting that SCAR is the primary regulator of Arp2/3-dependent morphological processes in Drosophila. In contrast, WASp is specifically required for the Arp2/3-dependent regulation of asymmetric cell divisions (Ben-Yaacov, 2001; Tal, 2002) a process that is independent of SCAR. These results demonstrate that SCAR and WASp perform generally nonoverlapping functions during Drosophila development and that the Arp2/3 complex can participate in distinct cell biological events in response to different regulators. Although SCAR and WASp can account for all characterized Arp2/3 complex functions in Drosophila, recent studies have described Arp2/3 complex regulators outside of the Scar/Wasp family (Jeng, 2001). Therefore, homologs of such elements (such as Cortactin and Eps15/Pan1p) may also play a role in Arp2/3-dependent processes during Drosophila development (Zallen, 2002).
A requirement for SCAR in the regulation of axon morphology in the Drosophila CNS has been demonstrated. The striking enrichment of SCAR protein in axons is consistent with a direct role for SCAR in axon development. In particular, the breaks in longitudinal and commissural axon bundles in SCAR mutant embryos may indicate a defect in axon growth. However, these phenotypes could also reflect defects in other aspects of nervous system formation, such as axon guidance, axon initiation, or neuronal differentiation. Morphological characterization of SCAR mutants at single neuron resolution will provide greater insight into the processes that require SCAR function (Zallen, 2002).
The CNS axon defects in SCAR mutant embryos resemble defects caused by simultaneous zygotic disruption of the Abl tyrosine kinase and a diverse set of elements including the Fasciclin I transmembrane protein, Armadillo/ß-catenin, Chickadee/profilin, and the Trio Rac/Rho guanine nucleotide exchange factor. Interestingly, Scar/WAVE-1 has been shown to associate with the SH3 domain of the Abl tyrosine kinase, suggesting that they may directly interact in vivo (Westphal, 2000). The observation that multiple zygotic mutations are required to replicate the SCAR phenotype is consistent with a model where SCAR functions downstream of multiple signaling pathways that converge on regulation of the actin cytoskeleton (Zallen, 2002).
The defects in axon morphology caused by reduction of maternal and zygotic SCAR are similar to those produced by zygotic disruption of Arp3 or simultaneous zygotic disruption of Arp3 and Arpc1 or SCAR and Wasp. These results suggest that SCAR, Wasp, and the Arp2/3 complex may affect a common process in neuronal development involving actin regulation. The contribution of both SCAR and Wasp to axon morphology could be explained by several possible mechanisms. In one model, SCAR and Wasp might regulate a common activity of the Arp2/3 complex, such as in the context of a specific actin structure or in contribution to bulk actin levels. Their functional differences in vivo could be achieved through differences in expression, activation, or subcellular localization. Alternatively, SCAR and Wasp could regulate distinct activities of the Arp2/3 complex, producing different actin structures that participate in diverse cell biological processes such as cell morphology (SCAR) and asymmetric cell division (Wasp). It will be interesting to examine how SCAR and Wasp intersect with regulators and effectors to achieve the specific organization of actin structures in different contexts (Zallen, 2002).
SCAR and the Arp2/3 complex regulate actin polymerization and organization in the blastoderm embryo. The dramatic reduction in actin levels of Drosophila Arpc1 mutants indicates that the Arp2/3 complex is an essential source of filamentous actin in the blastoderm embryo. This is consistent with experiments in other systems, where the Arp2/3 complex is required for actin polymerization in yeast actin patches (Pelham and Chang, 2001) and cell extracts in response to the Cdc42 GTPase (Ma, 1998; Mullins and Pollard, 1999) or the Listeria pathogen (Welch, 1997). These results also suggest that the SCAR regulator mediates this Arp2/3-dependent actin polymerization in the blastoderm. A similar reduction in filamentous actin is observed in Dictyostelium Scar mutants (Bear, 1998), and budding yeast Bee1 is required for actin polymerization at actin patch structures in a permeabilized cell assay (Lechler and Li, 1997). Together, these results demonstrate a conserved role for the Arp2/3 complex and WASp/Scar proteins in promoting actin polymerization in vivo as well as in vitro (Zallen, 2002).
In budding and fission yeast, inducible disruption of Arp2/3 complex function first leads to a cessation of actin patch movement followed by eventual actin patch dissolution (Winter, 1997; Pelham, 2001). Therefore, the Arp2/3 complex is required for the motility of actin structures and their formation. Similarly, Dictyostelium Scar mutants exhibit a selective disruption of specific actin structures that cannot easily be explained by an overall reduction of actin. Actin correctly localizes to the cell cortex and extends pseudopods as in wild type; however, leading edge actin fails to coalesce in response to chemoattractant, often leading to the aberrant formation of multiple pseudopods (Bear, 1998). These results suggest that Scar is involved in the dynamic organization of actin structures as well as their generation (Zallen, 2002).
An exciting possibility is that Scar and the Arp2/3 complex direct both the configuration and polymerization of actin in the Drosophila blastoderm. SCAR embryos in metaphase contain more than half the actin of wild-type embryos, yet this substantial amount of actin often fails to form even a discontinuous network of metaphase furrows. Instead, actin remains in aberrant surface structures that are not normally found at the surface of mitotic embryos. These observations suggest that SCAR plays a role in actin redistribution, perhaps through a local Arp2/3-dependent polymerization event that triggers a global cell cycledependent change in actin organization. This role of SCAR in the Drosophila embryo may be analogous to the reorganization of actin structures that occurs in other contexts, such as during cytokinesis or at the leading edge of migrating cells (Zallen, 2002).
A search of the sequenced Drosophila genome identified a single Scar/WAVE homolog (SCAR, corresponding to transcription unit CG4636) that maps to cytogenetic band 32C4-5 on the second chromosome. The structure of the SCAR transcript was determined by sequencing three ESTs from the Berkeley Drosophila Genome Project database. The 2,184 nucleotide SCAR transcript is predicted to encode a 613 amino acid protein possessing the major hallmarks of Scar/WAVE proteins (Zallen, 2002).
date revised: 15 September 2003
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