The gene coding for Drosophila Cortactin was cloned as a Polychaetoid interacting protein using the yeast two hybrid technique. An SH3 domain of approximately 60 amino acids dominates the C-terminal region of Cortactin. The SH3 domain is known to bind to a PXXP motif often found in proline-rich regions. The 139-amino acid region extending from amino acid 1115 to 1253 of Polychaetoid is sufficient for the interaction. This region contains four isolated PXXP motifs and three overlapping motifs (PFKPVPPPKP). The Cortactin SH3 domain binds to the PXXP motif located at the center of the Pyd C-terminal proline-rich domain, where three PXXP motifs are clustered (Katsube, 1998).
To examine the in vivo association of Pyd and Cortactin, Canton-S wild-type embryo lysates were precipitated with the rabbit anti-Drosophila Cortactin antiserum, the rabbit anti-Pyd antiserum, or the respective preimmune sera. The precipitates were analyzed by Western blotting. Western blotting with rat anti-Cortactin antiserum reveals that the Cortactin 105-kDa form is specifically coprecipitated by the anti-Pyd antiserum. These results clearly prove that Cortactin associates with Pyd in Drosophila embryo cells (Katsube, 1998).
Rabbit and rat antisera were raised against a GST-Cortactin fusion protein. Western blot analysis with the rabbit antiserum shows two prominent proteins with molecular masses of 105 and 110 kDa in all developmental stages. The expression of these proteins in adults is substantially less than those in other developmental stages. Western blotting with the rat antiserum give almost the same profile. The molecular weights of these proteins determined by SDS-PAGE are significantly larger than the predicted value (61 kDa). Similar observations of two forms of protein products with anomalous electrophoretic mobility have also been reported for vertebrate cortactin. The proline-rich domains may be responsible for their anomalous electrophoretic mobility (Katsube, 1998).
To examine the cellular localization, Cortactin was immunostained in epithelial cells of imaginal discs. The typical honeycomb-like images indicate that the protein distributes in a cell-cell contact-associated manner. To clarify the subcellular localization, the double stainings of Cortactin with Polychaetoid, F-actin, and E-cadherin (Shotgun) were conducted using a laser-scanning confocal microscope. Shotgun is a component of the adherens junction and localizes at the apicolateral region of epithelial cell junctions. The distribution of Polychaetoid partially overlaps with that of Shotgun and extends to the slightly basal region corresponding to the site of the septate junction. Colocalization of Cortactin, Polychaetoid, and Shotgun was evident, while the staining area of Cortactin in the periplasm seemed slightly broader than those of Polychaetoid and Shotgun. Colocalization of Cortactin and F-actin in a periplasmic region was also observed. Regarding the apical-basal axis, the distribution of Cortactin extended from the basal half side of the adherens junction to the more baso-lateral region (Katsube, 1998).
Myosin VI has been implicated in membrane dynamics in several organisms. The mechanism of its participation in membrane events is not clear. Spermatogenesis in Drosophila has been used to investigate myosin VI's in vivo role. Myosin VI colocalizes with and is required for the accumulation of the actin polymerization regulatory proteins, cortactin and arp2/3 complex, on actin structures that mediate membrane remodeling during spermatogenesis. In addition, dynamin localizes to these actin structures and when dynamin and myosin VI function are both impaired, major defects in actin structures are observed. It is concluded that during spermatogenesis myosin VI and dynamin function in parallel pathways that regulate actin dynamics and that cortactin and arp2/3 complex may be important for these functions. Regions of myosin VI accumulation are proposed as sites where actin assembly is coupled to membrane dynamics (Rogat, 2002).
Myosin VI function is required for membrane remodeling during the individualization step of spermatogenesis. During individualization, a syncytial membrane encasing a bundle of 64 spermatids is remodeled so that an individual membrane encases each of the 64 mature sperm. Myosin VI localizes to an actin complex, the individualization complex, which assembles at the spermatid heads at the start of individualization. This complex progresses from the spermatid heads to the tips of tails, remodeling membrane as it moves. Loss of myosin VI in the testis leads to the disruption of these actin complexes as they progress and, consequently, individualization is not completed (Rogat, 2002 and references therein).
Initially, during individualization, myosin VI accumulates in a particulate fashion along actin filaments as they assemble around the nuclei, but just as the actin individualization complex initiates movement away from the nuclei, myosin VI concentrates at the front of each actin cone. As the complex progresses down the length of the spermatid tails, myosin VI further concentrates into a tight band at the front of the actin cones. Myosin VI is also diffusely localized in front of the actin cones in association with the membrane and cytoplasm of the cystic bulge (Rogat, 2002).
The site at which myosin VI concentrates is the junction between a moving actin structure and a zone of active membrane remodeling. This location places myosin VI in an ideal position to link sites of remodeling to actin dynamics. Therefore, the localization of proteins that have been implicated in membrane/actin coordination was examined. One such protein is the actin-binding protein cortactin. Cortactin is thought to link membrane signaling proteins to actin dynamics by virtue of the ability of Cortactin to associate with both actin polymerization components and membrane-associated kinases (Rogat, 2002).
The distribution of cortactin was examined in individualizing spermatids with anti-Drosophila cortactin antibodies. Like myosin VI, cortactin concentrates at the front of actin cones, and double labeling of spermatids with cortactin and myosin VI antibodies shows that they colocalize at the front of each actin cone. Cortactin is also present on the cyst membrane. The distribution of cortactin in individualization complexes indicates that the fronts of the actin cones are sites where actin polymerization might be coupled with membrane dynamics. Myosin VI colocalization with cortactin at these sites suggests myosin VI may also be involved in these dynamics (Rogat, 2002).
To further demonstrate that the fronts of the actin cones are sites of regulated actin assembly, the distribution was examined of the arp2/3 complex and capping protein in individualizing spermatids. The arp2/3 complex is a complex of seven proteins that binds actin filaments and nucleates new actin filament assembly. Capping protein is a barbed-end actin-binding protein with a known role in regulating actin polymerization at sites where the arp2/3 complex promotes assembly. It is also concentrated in regions of dynamic actin assembly in many cell types. In individualizing spermatids, the arp2/3 complex, as demonstrated by arp3 and ARPC2/p34 staining, and capping protein, as demonstrated by CP-ß staining, concentrates at the front of actin cones. In both cases, staining was also visible generally through the cytoplasm of the cyst and along the actin cones. Double labeling experiments show that myosin VI colocalizes with concentrated arp3 and capping protein at the front of actin cones. The accumulation of proteins involved in actin polymerization at the front of the actin cones supports the idea that the zone where myosin VI concentrates is a zone of active actin assembly (Rogat, 2002).
The colocalization of cortactin, arp2/3 complex and myosin VI on individualization complexes prompted an examination of cortactin and arp2/3 complex distribution on individualization complexes in myosin VI mutants. Cortactin could be detected on actin individualization complexes in myosin VI mutants (jar1). However, its distribution was not normal. Cortactin was not concentrated at the front of the actin cones. Instead, it was weakly present uniformly along the cones. The complexes shown have a disrupted morphology and reduced actin staining, as is typically observed for progressed actin cones in myosin VI mutants. When early individualization complexes were examined in myosin VI mutants, no early complexes showed any concentration of cortactin at the front of cones. By contrast, in wild-type spermatids, some early individualization complexes had cortactin concentrated at the front and others did not. When doubly stained for myosin VI, those complexes with concentrated myosin VI also showed concentrated cortactin. It is concluded that myosin VI is required for the proper asymmetrical distribution of cortactin on actin cones (Rogat, 2002).
In contrast to the localization of cortactin on actin cones, its localization to cyst membrane was unaffected in myosin VI mutants, indicating that myosin VI is not required for its proper localization to cyst membrane (Rogat, 2002).
Defects were observed in arp2/3 complex localization in myosin VI mutants. Arp3 does not concentrate at the front of actin cones, either early or on progressed complexes, in myosin VI mutants. In addition, there appeared to be a higher level of arp3 staining in the cytoplasm of the cysts in myosin VI mutants in comparison to wild-type cysts. This may be because arp3 cannot concentrate on the actin cones and, instead, accumulates in the cytoplasm. Like arp3, ARPC2/p34 concentration at the front of actin cones is abolished in myosin VI mutants. Therefore, like cortactin, asymmetric distribution of the arp2/3 complex on the actin cones is dependent on myosin VI function. These findings support a role for myosin VI in regulating actin dynamics by participating in the localization of cortactin and arp2/3 complex at the front of the individualization complex (Rogat, 2002).
Mutations in the cortactin locus were generated by imprecise excision of a P-element located upstream of the transcription start site. One of the four deletion alleles precisely removes the cortactin transcription unit (cortM7) and two others most of the coding region (cortD4 and cortA4). All four alleles show the same phenotypes, but the M7 and D4 alleles were used for further analysis. The cortactin mutant flies are homozygous viable and show no visible abnormalities. The stock becomes completely homozygous without selection, showing that there is no requirement for maternal contribution of cortactin, nor is there a large growth disadvantage due to loss of cortactin. However, it was noticed that the females had somewhat reduced fertility and therefore oogenesis was examined in more detail (Somogyi, 2004).
During oogenesis, development proceeds in egg chambers consisting of centrally located germ line cells (15 'nurse cells' and one oocyte) surrounded by a simple monolayer epithelium, the follicular epithelium. At stage 9, a small cluster of follicle cells called border cells, delaminate from the follicular epithelium, invade the germ line cluster and migrate to the oocyte. Cortactin is specifically enriched in migrating border cells. Cortactin is also enriched at the actin rich structures called ring canals. Ring canals are formed early in oogenesis in place of the cleavage furrow after incomplete cytokinesis of germ line cells. Proper function of ring canals is necessary for transfer of material from nurse cells to the oocyte. Finally, Cortactin protein is detected along the cortex of the follicle cells (Somogyi, 2004).
A number of specific defects were observed in cortactin mutants. One cortactin phenotype is a mild defect in 'dumping', transfer of bulk cytoplasmic material from nurse cells to the oocyte. This phenotype is similar to that observed in Src64 mutants, but is also seen in other mutants. In the case of Src64, the defect is correlated to the presence of Src64 protein at the ring canals and to reduced size of the ring canals. Cortactin is also present at ring canals. To determine whether cortactin affects ring canal morphogenesis, their size was quantified at stage 10. Ring canal size is significantly reduced in the cortactin mutant relative to wild type. Dumping defects usually result in smaller eggs. Eggs from cortactin mutant mothers and from Src64 mutant mothers are on average smaller than wild type. The hatching rate of the eggs from mutant mothers is also decreased. Thus, mutations in cortactin affect the actin rich ring canals, and processes dependent on function of ring canals, in a manner similar to mutations in Src64. Mutations in components of the Arp2/3 complex (Arpc1 or Arp3 mutants) are also known to specifically affect ring canal morphogenesis (Somogyi, 2004).
With low penetrance (around 6% of stages 5-9 egg chambers), cortactin mutants also display discontinuities in the follicular epithelium, which is not observed in the wild type situation. A similar phenotype has been observed in other mutants such as crumbs, where the affected protein is thought to have a basic function in establishing the epithelium. The phenotype suggests that Cortactin has a role in epithelial integrity. The low penetrance indicates that this function mostly can be compensated by other proteins (Somogyi, 2004).
Border cell migration is also abnormal in cortactin mutants. Since cortactin has been proposed to be important for migration of normal and invasive mammalian cells, this defect seemed particularly interesting. To quantify border cell migration, the progression of the cluster was compared to the stretching of the epithelium on the surface of the egg chamber as well as to the growth of the oocyte. In cortactin homozygous mutant females, border cell migration is delayed. However, migration does not arrest completely, since the clusters manage to reach their target, the oocyte, at stage 10. To determine whether the delay is due to a defect in the border cells themselves or in the migration substrate, the germ line cells, mosaic egg chambers were analyzed. When follicle cells including border cells are mutant for cortactin, the delay is apparent. In contrast, if only germ line cells are mutant for cortactin, the migration is normal. Thus, cortactin is required cell autonomously for border cell migration to occur efficiently (Somogyi, 2004).
To gain some insight into how Cortactin might affect migration of border cells, how follicle cells respond to overexpression of Cortactin was examined. The follicle cells forming the simple monolayer epithelium that covers the oocyte are related to border cells, but normally express lower levels of Cortactin. Clones of follicle cells expressing high levels of Cortactin show increased accumulation of F-actin. Interestingly, these cells also form short, Cortactin- and F-actin-rich protrusions or filopodia. Thus, Cortactin overexpression is sufficient to promote actin filament accumulation. It is also sufficient to induce formation of short cellular extensions in epithelial cells. These cellular effects may be mechanistically related to the ability of mammalian Cortactin to promote formation of membrane protrusions and membrane ruffles or waves in cultured cells (Somogyi, 2004).
There were several reasons to suspect that the effect of Cortactin on the actin cytoskeleton could be related to effects of RTKs. Border cell migration is guided by two RTKs, namely PDGF/VEGF receptor (PVR) and EGFR. Also, an activated form of PVR induces robust formation of actin-rich extensions in follicle cells in a Rac dependent manner. Finally, mammalian Cortactin has been suggested to act as a link between RTKs such as PDGF receptor and the actin cytoskeleton. Therefore the effect of PVR signaling on Cortactin protein was examined in the follicular epithelium. Overexpression of wild type PVR is sufficient to increase signaling in follicle cells slightly, resulting in a small increase in F-actin accumulation in the cell. This is most visible at the basal F-actin network. PVR overexpression also results in clear recruitment and/or stabilization of Cortactin at the cell cortex. Cortactin protein is not simply recruited by the increased amount of F-actin; the subcellular localization of Cortactin is distinct from that of F-actin. In addition, the level and the localization of other actin-associated proteins such as moesin and alpha-spectrin are not visibly affected by PVR overexpression. Expression of a constitutive active form of PVR (lambda-PVR) results in more robust F-actin accumulation but also disruption of the normal cell shape. The activated receptor is not restricted to the cell cortex but is present in vesicles throughout the cell. The constitutive active PVR also induces accumulation of Cortactin throughout the cell. Thus, PVR activation in follicle cells affects the accumulation and subcellular localization of Cortactin protein, primarily resulting in more Cortactin at the cell cortex of normal epithelial cells (Somogyi, 2004).
The ability of Cortactin to induce F-actin accumulation and filopodia formation in conjunction with the effect of PVR on Cortactin protein suggested that Cortactin might act downstream of PVR with respect to control of the actin cytoskeleton. To determine if this might be the case, an epistasis experiment was performred. The effect of activated PVR (lambda-PVR) on F-actin accumulation and cell shape in follicle cells was scored using three categories of severity. Quantification was done by blindly scoring severity of the phenotype in many egg chambers. In each experiment follicle cells that were mutant for cortactin were compared to a control, wild type background. A small, but statistically significant decrease was seen in the severity of the lambda-PVR induced phenotypes in the cortactin mutant background. This result is consistent with Cortactin acting downstream of PVR, but also shows that the effect of PVR on the actin cytoskeleton does not strictly require Cortactin. Another factor that appears to act downstream of PVR is the Rac activator Mbc (related to DOCK180 and Ced-5). In the same assay, removal of mbc has a much more pronounced effect. Activation of Rac can cause translocation of Cortactin to the cell periphery in mammalian cells (Weed, 1998). Thus, cortical Cortactin accumulation could be one of the downstream effects of Rac activation by PVR. In conclusion, Cortactin appears to contribute to the effects of PVR on actin, but is largely redundant with other factors. A contributing, but not essential, function is also consistent with cortactin not being an essential gene (Somogyi, 2004).
Expression of an activated form of Src (Src42CA) in border cells and other follicle cells shows a phenotype similar to that of activated PVR. It completely blocks border cell migration and disrupts cell shape and the actin cytoskeleton of follicle cells. Src64 has a specific function in the female germ line, which coincides with a function of Cortactin as discussed above. Src42 appears to function more generally in somatic cells and is required for viability. Unfortunately, it is technically not feasible to make Src42 mutant clones to determine whether Src42 function is required in border cells. However, whether Cortactin might act downstream of activated Src42 could be examined by performing an epistasis experiment equivalent to that with activated PVR. Removal of cortactin results in a small, but significant, decrease in the severity of the activated Src-induced phenotype. This is consistent with a role of Cortactin downstream of Src. It also shows that Src can affect the cytoskeleton independently of Cortactin (Somogyi, 2004).
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