fused (fu) is a maternal effect segment polarity gene of Drosophila melanogaster. In addition, fu females have tumorous ovaries. Two ethyl methanesulfonate mutageneses were carried out in order to isolate suppressors of the fu phenotype. A new gene, Suppressor of fused [Su(fu)], was identified. It is located in the 87C8 region of the third chromosome. Su(fu) displays a maternal effect and is also expressed later in development. Although Su(fu)LP is a complete loss-of-function mutation, it is homozygous viable and produces no phenotype by itself. Su(fu) fully suppresses the embryonic and adult phenotypes of fu mutants. Su(fu) mutations are semidominant and a Su(fu)+ duplication has the opposite effect, enhancing the fused phenotype. It is proposed therefore that the Su(fu)+ product is involved in the same developmental step as the Fu+ kinase. Thus, a new gene interacting with the segment polarity pathway was identified using an indirect approach (Preat, 1992).
Su(fu) enhances a cos-2 phenotype and cos-2 mutations interact with fu in a way similar to Su(fu). A close relationship might exist between fu, Su(fu) and cos-2 throughout development. The Fu+ kinase might be a posterior inhibitor of Costal-2+ while Su(fu)+acts as an activator of Costal-2+. The expression pattern of wingless and engrailed in fu and fused-Su(fu) mutant embryos supports this interpretation (Preat, 1993).
Suppressor of fused, isolated as a mutation suppressing the fused phenotype, interacts with fused in the fused segment polarity function. Fused and Suppressor of fused could act through a competitive posttranslational modification of a common target in the hedgehog signaling pathway. The amorphic Su(fu) mutation is viable, shows a maternal effect and displays no phenotype by itself. The Su(fu) gene encodes a 53-kD protein, contains a PEST sequence and shows no significant homologies with known proteins. Proper development requires a fine tuning of the genetic doses of fu and Su(fu), both maternally and zygotically (Pham, 1995).
fused is a segment-polarity gene encoding a putative serine-threonine kinase. In a wild-type context, all fu mutations display the same set of phenotypes. Nevertheless, mutations of the Suppressor of fused [Su(fu)] gene define three classes of alleles: fuO, fuI, and fuII. The Fused (Fu) protein functions in vivo as a kinase. The N-terminal kinase and the extreme C-terminal domains are necessary for Fu+ activity, while a central region appears to be dispensable. A striking correlation is observed between the molecular lesions of fu mutant alleles and the phenotype displayed as a result of the interaction of these alleles with Su(fu). Indeed, fuI alleles, which are suppressed by Su(fu) mutations, are defined by inframe alterations of the N-terminal catalytic domain, whereas the C-terminal domain is missing or altered in all fuII alleles. An unregulated FuII protein, which can be limited to the 80 N-terminal amino acids of the kinase domain, would be responsible for the neomorphic costal-2 phenotype displayed by the fuII-Su(fu) interaction. It is proposed that the Fu C-terminal domain can differentially regulate the Fu catalytic domain according to cell position in the parasegment (Therond, 1996).
The Suppressor of fused [Su(fu)] gene encodes a protein with a PEST sequence involved in rapid protein turn-over (Pham, 1995). Fused is phosphorylated in response to the Hh signal. A large protein complex that includes Cubitus interruptus, Costal-2 and Fused binds to microtubules and has been implicated in the regulation of Ci cleavage and accumulation, and may be involved in mediating the Hh signal. Although Su(fu) activity is apparently dispensable in a wild-type background, its absence fully suppresses all the fused mutant phenotypes. These data suggest that the activation of Fused in cells receiving the Hh signal relieves the negative effect of Su(fu) on the pathway (Alves, 1998 and references).
The roles of Fused and Su(fu) proteins were examined in the regulation of Hh target gene expression in wing imaginal discs, by using different classes of fu alleles and an amorphic Su(fu) mutation. The fused phenotype consists of a vein 3 thickening and vein 4 disappearance with reduction of the intervein region. At the wing margin, the anterior double row bristles reach the fourth vein. Fused protein is present throughout the entire wing level, but its level is much higher in the anteior compartment. In contrast, fused transcripts are uniformly distributed, suggesting that fused is regulated post-transcriptionally. Observations using fused clones indicate that only fused minus clones located in the region extending between veins 3 and 4 generate a mutant phenotype, consisting of extra-veins, which often bear campaniform sensillae characteristic of vein 3. Thus Fused kinase activity is required at the anterior/posterior (AP) boundary in the anterior compartment. At the AP boundary, Fu kinase activity is involved in the maintenance of high ptc expression and in the induction of late anterior engrailed expression. These combined effects can account for the modulation of Ci accumulation and for the precise localization of the Dpp morphogen stripe. Here, at the AP boundary, Hh signal activates the Fu kinase, leading to a modified active form of Ci required for anterior en expression and high ptc expression. Su(fu) suppresses all fused phenotypes associated with the AP boundary, suggesting that Su(fu) normally functions to antagonize the effects of Fused (Alves, 1998).
Two classes of fused mutants are described with respect to more anterior cells, which are so distant from the AP boundary that they do not receive Hh signal. Class I and class II fused alleles encode structurally different proteins; fused class I alleles encode mutant proteins altered in the catalytic domain but containing at least the 300 C-terminal amino acids, while class II alleles encode proteins truncated in the C-terminal, non-catalytic domain. In class II fused mutant discs, but not in class I mutants, abnormal dpp-lacZ expression is detected at the anterior-dorsal part of the disc in the presumptive hinge region of the wing. This ectopic expression is not correlated with any phenotype, but an interaction of fused with Su(fu) is observed. This interaction consists of an overgrowth of the anterior compartment accompanied by ectopic dpp-lacZ. Taken together, these results demonstrate that whereas at the AP boundary Fu and Su(fu) have opposite effects on the levels of ptc and dpp expression, in the anterior compartment, class II fused mutant products activate dpp expression and this effect is enhanced when Su(fu) is absent. Thus Fu plays a role independent of its kinase function (but dependent on its C-terminal domain) in the regulation of Ci accumulation in the anterior compartment. In these cells, Fu may be involved in the stabilization of a large protein complex that is probably responsible for the regulation of Ci cleavage and/or targeting to nucleus. In the anterior compartment, no Hh signal is received and Ci cleavage gives rise to a short Ci form that represses dpp expression (Alves, 1998).
The Drosophila protein Shaggy (Sgg, also known as Zeste-white3, Zw3) and its vertebrate ortholog glycogen synthase kinase 3 (GSK3) are inhibitory components of the Wingless (Wg) and Wnt pathways. Sgg is also a negative regulator in the Hedgehog (Hh) pathway. In Drosophila, Hh acts both by blocking the proteolytic processing of full-length Cubitus interruptus, Ci (Ci155), to generate a truncated repressor form(Ci75), and by stimulating the activity of accumulated Ci155. Loss of sgg gene function results in a cell-autonomous accumulation of high levels of Ci155 and the ectopic expression of Hh-responsive genes including decapentaplegic and wg. Simultaneous removal of sgg and Suppressor of fused, Su(fu), results in wing duplications similar to those caused by ectopic Hh signaling. Ci is phosphorylated by GSK3 after a primed phosphorylation by protein kinase A (PKA), and mutating GSK3 phosphorylation sites in Ci blocks its processing and prevents the production of the repressor form. It is proposed that Sgg/GSK3 acts in conjunction with PKA to cause hyperphosphorylation of Ci, which targets it for proteolytic processing, and that Hh opposes Ci proteolysis by promoting its dephosphorylation (Jia, 2002).
The activity of Ci155 is regulated by several mechanisms including attenuation by Su(fu). Whereas loss of Su(fu) function does not cause any significant phenotypes, it dramatically enhances sgg- phenotypes. For example, anterior sgg;Su(fu) double-mutant clones organize wing duplication, whereas sgg single-mutant clones form only small outgrowths. In wing discs, anterior sgg;Su(fu) double-mutant cells activate low levels of ptc, which is not ectopically expressed in sgg single-mutant cells. In leg discs, anterior sgg;Su(fu) double-mutant cells express ptc and high levels of wg. Hence, Ci155 accumulated in sgg- cells is largely inactive and its activity is stimulated by removal of Su(fu) function (Jia, 2002).
The mechanism by which the secreted signaling molecule Hedgehog (Hh) elicits concentration-dependent transcriptional responses from cells is not well understood. In the Drosophila wing imaginal disc, Hh signaling differentially regulates the transcription of target genes decapentaplegic (dpp), patched (ptc) and engrailed (en) in a dose-responsive manner. Two key components of the Hh signal transduction machinery are the kinesin-related protein Costal2 (Cos2) and the nuclear protein trafficking regulator Suppressor of Fused [Su(fu)]. Both proteins regulate the activity of the transcription factor Cubitus interruptus (Ci) in response to the Hh signal. This study analyzed the activities of mutant forms of Cos2 in vivo and found effects on differential target gene transcription. A point mutation in the motor domain of Cos2 results in a dominant-negative form of the protein that derepresses dpp but not ptc. Repression of ptc in the presence of the dominant-negative form of Cos2 requires Su(fu), which is phosphorylated in response to Hh in vivo. Overexpression of wild-type or dominant-negative cos2 represses en. These results indicate that differential Hh target gene regulation can be accomplished by differential sensitivity of Cos2 and Su(Fu) to Hh (Ho, 2005).
How Hh differentially regulates target genes is central to understanding how one signal generates multiple downstream effects and activates different target genes at different concentrations. Using mutant forms of Cos2, this study has investigated how components of the Hh signal transduction pathway form a sensitive switch that governs the difference between dpp-expressing cells and cells expressing both ptc and dpp. To assess the importance of the putative motor, neck and cargo domains to Cos2 in Hh signaling, deletion constructs of Cos2 were made lacking each domain. In addition, the Ser182 of Cos2 was changed to Asn (S182N) in the P-loop, which in other kinesins gives rise to a dominant-negative form that lacks ATPase activity. Using these mutant forms of Cos2, the roles of Cos2 and Su(fu) were investigated in the regulation of the Hh target genes (Ho, 2005).
Cos2 is required for the activation of the target gene en, and S182N expression or cos2-overexpression can block this activation, despite the presence of high levels of Hh. Cos2 has been proposed to act not only as a scaffold for Hh signaling components, but as a sensor of the Hh signal, playing a dual role as both an activator and a repressor of the pathway. Mutation of the P-loop of Cos2, which is designed to disrupt the ATPase activity of the protein, profoundly affects the activity of the protein, and through that the outcome of the pathway, in agreement with a role for Cos2 as a sensor for Hh signal (Ho, 2005).
Conventional kinesins require ATPase activity in order to move along microtubules. Studies have shown that mutation of the conserved Ser or Thr at a precise position in the P-loop causes the protein to become immobile, locking itself and its cargo along microtubules prematurely, before the final intracellular destination for the kinesin has been reached. Expression of such kinesin mutants specifically inhibits the movement of its endogenous partner, but not the movements of other kinesins or dyneins along the microtubule This knowledge about kinesins and the importance of their P-loops to design the equivalent mutation in Cos2. The mutation of amino acid 182 of Cos2 to a conserved Thr does not detectably alter the function of Cos2 in vivo, while mutation of the same residue to Asn clearly interferes with normal Cos2 activity. This clearly suggests that Cos2 is likely to use ATPase activity for either locomotion or conformational changes in response to Hh signaling. The movement of Cos2 along microtubules in vitro has yet to be demonstrated, but the importance of intracellular localization of various Hh signaling components has been clearly demonstrated. Among the examples: in response to Hh, Smo accumulates at the plasma membrane, and associates with Cos2 and Fu; Ci accumulates in the nucleus in response to Hh signaling; and in the absence of Hh signal, Smo is located in internal membranes in the cytoplasm of responding cells, and Ci is continually exported from the nucleus, phosphorylated by kinases, and processed into CiR by the proteasome. How do the components arrive at the appropriate places to affect the appropriate response? As a binding partner for all of these components and as a kinesin-related protein, Cos2 is in a unique position to orchestrate some of these events. Ideas for how it may accomplish are given below (Ho, 2005).
The data suggest that the activities of Cos2 and Su(fu) are independently regulated by different concentrations of Hh along the gradient that forms from posterior to anterior. In the anterior cells distant from the AP boundary, little or no Hh is received and target genes are silent. In these cells, Cos2 is required for proteolytic processing of Ci into its repressor form and possibly for the delivery of CiFL for lysosomal degradation. The data suggest that Cos2 requires an intact P-loop for its role in these events. Cos2 ATPase activity may be inhibited in cells receiving very low levels of Hh, preventing Ci proteolysis and stabilizing CiFL. The stabilization of CiFL results in the activation of dpp. Nearer the AP border, where higher levels of Hh are received, Su(fu) becomes phosphorylated, inactivating its negative regulatory hold on Ci, while inhibition of the ATPase activity of Cos2 continues to allow stabilization of Ci. In this situation, ptc and dpp are transcribed. Finally, at the highest levels of Hh signaling adjacent to the AP border, Cos2 is required for activation of the pathway and the expression of en. S182N expression, or cos2 over-expression, inhibits the induction of en by endogenous Hh in these cells. The elements of this model are addressed below (Ho, 2005).
Ci plays a central role in determining which genes are repressed or activated in response to different concentrations of Hh. In order to activate target genes such as dpp or ptc, Ci must be stabilized in its full-length form. In wild-type discs, Hh stabilizes Ci by antagonizing molecular events that reduce the concentration of nuclear CiFL. In addition to the constitutive nuclear export of Ci, there are two ways CiFL concentration is reduced: full-length Ci is proteolytically processed into a repressor form; and CiFL is degraded by a lysosome-mediated process involving a novel protein called Debra. In these experiments, the stabilization of CiFL was accomplished by expressing S182N in responsive cells, which antagonizes Cos2 repressor activity and results in the accumulation of high levels of CiFL, with minimal effects on the levels of CiR. This same type of differential effect on CiR and CiFL is accomplished by Debra, which causes the lysosomal degradation of CiFL without affecting the production of CiR. Cos2 and Debra may act in concert to destabilize CiFL, while Cos2 may also aid in the production of CiR via a Debra-independent mechanism. This would involve presenting Ci to the kinases, PKA, CKI and GSKß (Shaggy) for phosphorylation and processing by the proteasome. Since Debra regulates Ci stability in limited areas of the wing disc but S182N can stabilize Ci throughout the anterior compartment, it is likely that S182N interferes with both Debra-dependent and Debra-independent mechanisms of Ci stability to achieve the observed effect: cell-autonomous stabilization of CiFL leading to derepression of dpp (Ho, 2005).
These results suggest that Cos2 may use its ATPase activity to transport Ci to a location where it becomes phosphorylated in preparation for processing, or to the site of processing itself. Alternatively, the ATPase activity may be important for regulating the conformation of Cos2 and its binding to partners such as Smo, Su(fu), Fu and Ci, which would be a novel role for the P-loop in a kinesin-related protein. The S182N mutation may lock Cos2 in a conformation that changes association with binding partners. For example, S182N may decrease the ability of Cos2 to bind Ci, releasing Ci from the cytoplasm, resulting in an increased level of CiFL in the nucleus and the activation of dpp (Ho, 2005).
The human ortholog of Suppressor of fused is a tumor suppressor gene. Su(fu) can associate with Ci, and with the mammalian homologs of Ci, the Gli proteins, through specific protein-protein interactions. Through these interactions, Su(fu) controls the nuclear shuttling of Ci and Gli, as well as the protein stability of CiFL and CiR. Flies homozygous for Su(fu) loss-of-function mutations are normal, so the importance of Su(fu) becomes evident only when other gene functions are thrown out of balance, as in a fu mutant background, with extra or diminished Hh signaling caused by ptc, slimb and protein kinase A mutations or when altered Cos2 is produced (Ho, 2005).
To activate ptc transcription in the wing disc, two conditions have to be met simultaneously: CiFL must be stabilized, and the activity of Su(fu) must be reduced. Removal of Su(fu) changes S182N from a ptc repressor into a ptc activator. Removal of Su(fu) may result in the modification, activation or relocalization of CiFL, or in further sensitizing the system to stabilized CiFL. In Su(fu) homozygous animals, the quantity of CiFL and CiR proteins is greatly diminished, and Su(fu) mutant cells are more sensitized to the Hh signal. The lower levels of both CiFL and CiR in mutant Su(fu) cells may contribute to the sensitivity of these cells to Hh, since a small Hh-driven change in the absolute concentration of either form of Ci would result in a significant change in the ratio between the two proteins. Both CiFL and CiR bind the same enhancer sites, so their relative ratio is likely to be important in determining target gene expression. S182N expression tips the ratio of CiFL to CiR toward CiFL, and reducing the absolute quantities of both Ci isoforms by removing Su(fu) will enhance this effect. Furthermore, Su(fu) binds Ci and sequesters it in the cytoplasm in a stoichiometric manner Reducing the amount of Su(fu) should release more CiFL to the nucleus to activate ptc (Ho, 2005).
The activity of Su(fu) must be regulated or overcome so that target genes can be activated at the right times and places in response to Hh. The regulation of Su(fu) activity may occur by Hh-dependent phosphorylation. A phosphoisoform of Su(fu), Su(fu)-P, was detected in discs where GAL4 was used to drive extra Hh expression. At high concentrations of Hh, the phosphorylation of Su(fu) is not antagonized by overexpression of cos2 or either of the cos2 mutants, suggesting that phosphorylation of Su(fu) occurs independently of Cos2 function. One kinase involved in the phosphorylation of Su(fu) is the Ser/Thr kinase Fused, a well-established component of Hh signal transduction. It is not known whether the phosphorylation of Su(fu) by Fu is direct or indirect (Ho, 2005).
The phosphorylation state of Su(fu) may be an important factor in determining Hh target gene activity. Phosphorylation of an increasing number of Su(fu) molecules with increasing Hh signal may gradually release Ci from all of the known modes of Su(fu)-dependent inhibition, such as nuclear export and recruitment of repressors to nuclear Ci, leading to higher levels of CiFL in the nucleus and the activation of Hh target genes such as ptc (Ho, 2005).
Anterior en expression was used as an in vivo reporter of high levels of Hh signaling. cos2 mutant cells at the AP boundary fail to activate en, suggesting that Cos2 plays a positive regulatory role in en regulation. S182N, S182T and Cos2 overexpression mimics the cos2 loss-of-function condition with respect to en: en remains off in these cells. One interpretation of these data is that all the Cos2 proteins are able to associate with another pathway component, such as Smo, and overproduction of any of them inactivates some of the Smo in non-productive complexes not capable of activating en (Ho, 2005).
In contrast to the activity of all the other mutations generated, deletion of the C terminal domain creates a protein (Cos2DeltaC) that represses normal dpp, ptc and en expression in the wing disc. In this in vivo assay, Cos2DeltaC acts just like wild-type Cos2. A similar deletion has been shown to retain function in cell culture assays. This mutant, expressed under the control of its endogenous promoter, rescues the lethality and wing duplication phenotypes of a cos2 loss-of-function allele over a cos2 deficiency. The results of the rescue experiment bring up a new possibility: that the C-terminal domain of Cos2, and the Cos2-Smo interaction via the C terminus of Cos2, is not necessary for repressor activities of Cos2. Alternatively, Cos2DeltaC could complement or boost the activity of the hypomorphic allele cos211, which was used for the rescue experiment (Ho, 2005).
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date revised: 2 February 2023
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