Interactive Fly, Drosophila

shaggy


EVOLUTIONARY HOMOLOGS


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GSK-3 in Fish

Zebrafish was used as a model system for the study of vertebrate dorsoventral patterning. A maternally expressed and dorsal organizer localized member of the frizzled family of wnt receptors was isolated. Both wild-type and dominant loss-of-function molecules in misexpression studies demonstrate frizzled function is necessary and sufficient for dorsal mesoderm specification. frizzled activity is antagonized by the action of GSK-3, and GSK-3 is also required for zebrafish dorsal mesoderm formation. frizzled cooperatively interacts with the maternally encoded zebrafish Wnt8 protein in dorsal mesodermal fate determination. This frizzled-mediated wnt pathway for dorsal mesoderm specification provides the first evidence for the requirement of a wnt-like signal in vertebrate axis determination (Nasevicius, 1998).

The mechanism of early dorso-ventral axis specification in zebrafish embryos is not well understood. While beta-catenin has been clearly implicated as a determinant of the axis, the factors upstream and downstream of beta-catenin in this system are not defined. Unlike Xenopus, where a sperm-induced cortical rotation is used to localize beta-catenin on the future dorsal side of the embryo, zebrafish do not have an obviously similar morphogenetic movement. A GSK-3 (glycogen synthase kinase-3) binding protein (GBP) has been identified as a novel member of the Wnt pathway required for maternal dorsal axis formation in Xenopus. GBP stabilizes beta-catenin levels by inhibiting GSK-3 and potentially provides a link between cortical rotation and beta-catenin regulation. Since zebrafish may use a different mechanism for regulating beta-catenin, it was asked whether zebrafish also express a maternal GBP. The zebrafish GBP gene has been isolated and shown to be maternally expressed. It is present as mRNA ubiquitously throughout early embryonic development. Over-expression of zebrafish GBP in frogs and fish leads to hyper-dorsalized phenotypes, similar to the effects resulting from over-expression of beta-catenin, indicating that components upstream of beta-catenin are conserved between amphibians and teleosts. Also examined was whether Tcf (T cell factor) is functional in zebrafish embryos. As in frogs, ectopic expression of a dominant negative form of XTcf-3 ventralizes zebrafish embryos. In addition, ectopic beta-catenin expression activates the promoter of the Tcf-dependent gene siamois, indicating that the step immediately downstream of beta-catenin is also conserved between fish and frogs (Sumoy, 1999).

GSK-3 in Xenopus

Glycogen synthase kinase-3ß is a negative regulator of the wnt signaling pathway that plays a central role in the development of invertebrates and vertebrates; loss of function and dominant negative mutations in GSK-3ß lead to activation of the wnt pathway in Drosophila and Xenopus. Evidence is provided that lithium activates downstream components of the wnt signaling pathway in vivo, leading to accumulation of ß-catenin protein. This activation of the wnt pathway is a consequence of inhibition of GSK-3ß by lithium. Using a novel assay for GSK-3ß in oocytes, it was shown that lithium inhibits GSK-3ß from species as diverse as Dictyostelium and Xenopus, providing a biochemical mechanism for the action of lithium on the development of these organisms. Lithium treatment also leads to activation of an AP-1-luciferase reporter in Xenopus embryos, consistent with previous observations that GSK-3ß inhibits c-jun activity. Activation of the wnt pathway with a dominant negative form of GSK-3ß is inhibited by myo-inositol, similar to the previously described effect of coinjecting myo-inositol with lithium. The mechanism by which myo-inositol inhibits both dominant negative GSK-3ß and lithium remains uncertain (Hedgepeth, 1997).

Dorsal axis formation in the Xenopus embryo can be induced by the ectopic expression of several Wnt family members. A kinase-dead mutant of Xgsk-3, the Xenopus homology of shaggy, has a dominant negative effect and mimics the ability of Wnt to induce a secondary axis by induction of an ectopic Spemann organizer. In other words, a mutations in Xgsk-3 mimics Wnt just as mutation on shaggy in Drosophila mimics the effects of wingless signaling. The Xgsk-3 mutant, like Wnt, induces dorsal axis formation when expressed in the deep vegetal cells, that usually do not contribute to the axis. Dorsal fate is actively repressed by Xgsk-3, which must be inactivated for dorsal axis formation to occur (Pierce, 1995 and Dominguez, 1995).

Elimination of ß-catenin, the Xenopus homolog of Armadillo, eliminates dorsal structures, while injection of Plakoglobin induces ectopic heads. Overexpression of Xgsk-3 disrupts anterior ectodermal patterning in Xenopus causing expansion of the cement gland and expansion of the anterior domain of Xotx2, a homolog of Orthodenticle. Xgsk-3 mutation increases ectodermal responsiveness to mesoderm, synergizing with Noggin (a protein that binds to and inactivates BMP-4, the vertebrate homolog of decapentaplegic), a secreted factor expressed in the dorsal mesoderm that can induce cement gland and the expression of neural genes in isolated ectoderm (Pierce, 1996).

The serine/threonine kinase Xgsk-3 and the intracellular protein beta-catenin are necessary for the establishment of the dorsal-ventral axis in Xenopus. Although genetic evidence from Drosophila indicates that Xgsk-3 is upstream of beta-catenin, direct interactions between these proteins have not been demonstrated. Phosphorylation of beta-catenin in vivo requires an in vitro amino-terminal Xgsk-3 phosphorylation site, which is conserved in the Drosophila protein Armadillo. beta-catenin mutants lacking this site are more active in inducing an ectopic axis in Xenopus embryos and are more stable than wild-type beta-catenin in the presence of Xgsk-3 activity, supporting the hypothesis that Xgsk-3 is a negative regulator of beta-catenin, acting through the amino-terminal site. Inhibition of endogenous Xgsk-3 function with a dominant-negative mutant leads to an increase in the steady-state levels of ectopic beta-catenin, indicating that Xgsk-3 functions to destabilize beta-catenin and thus decrease the amount of beta-catenin available for signaling. The levels of endogenous beta-catenin in the nucleus increases in the presence of the dominant-negative Xgsk-3 mutant, suggesting that a role of Xgsk-3 is to regulate the steady-state levels of beta-catenin within specific subcellular compartments (Yost, 1996).

The molecular nature of the primary dorsalizing inducing event in Xenopus is controversial and several secreted factors have been proposed as potential candidates: Wnts, Vg1, Activin and Noggin. However, recent studies have provided new insight into the activity of the dorsalizing region, called the Nieuwkoop Center. Two properties of the Nieuwkoop Center have been used to evaluate the dorsalizing activity of the four secreted factors Wnt8, Vg1, Activin and Noggin: (1) the activity of this dorsalizing center involves an entire signal transduction pathway that requires maternal ß-catenin, and (2) a transcription factor with potent dorsalizing activity, Siamois, is expressed within the Nieuwkoop Center.

The requirement for ß-catenin was tested by coexpressing a cadherin, which sequesters ß-catenin at the cell membrane and specifically blocks its intracellular signaling activity. Of the four growth factors, only Wnt is sensitive to inhibition of ß-catenin activity and only Wnt can induce Siamois expression. Therefore, Wnt is able to induce a bonafide Nieuwkoop Center, while Vg1, Activin and Noggin probably induce dorsal structures by a different mechanism. GSK acts upstream of ß-catenin, similar to the order of these components in the Wingless pathway in Drosophila. ß-catenin induces expression of Siamois and the free signaling pool of ß-catenin is required for normal expression of endogenous Siamois. It is concluded that the sequence of steps in the signaling pathway is initiated by Wnt, which acts to inhibit GSK. GSK in turn acts to inhibit ß-catenin which acts to activate Siamois (Fagotto, 1997).

The expression of glycogen synthase kinase-3beta has been examined in oocytes and early embryos of Xenopus and the protein is found to be developmentally regulated. In resting oocytes, GSK-3beta is active and it is inactivated on maturation in response to progesterone. GSK-3beta inactivation is necessary and rate limiting for the cell cycle response to this hormone and the subsequent accumulation of beta-catenin. Overexpression of a dominant negative form of the kinase accelerates maturation, as does inactivation by expression of Xenopus Dishevelled or microinjection of an inactivating antibody. Cell cycle inhibition by GSK-3beta is not mediated by the level of beta-catenin or by a direct effect on either the MAP kinase pathway or translation of mos and cyclin B1. These data indicate a novel role for GSK-3beta in Xenopus development: in addition to controlling specification of the dorsoventral axis in embryos, it mediates cell cycle arrest in oocytes. GSK-3beta is not the only kinase involved in G2 arrest in oocytes. Inactivation of PKA is both necessary and sufficient to induce meiotic maturation of Xenopus oocytes. One could imagine that PKA and GSK-3beta may be involved synergistically in mediating G2 arrest, by phosphorylating a common target inhibitory for cell cycle progression, and/or by preventing accumulation of an activator of cell cycle progression. GSK-3beta is bypassed by cyclin B microinjection (Fisher, 1999).

Cortical rotation and concomitant dorsal translocation of cytoplasmic determinants are the earliest events known to be necessary for dorsoventral patterning in Xenopus embryos. The earliest known molecular target is beta-catenin, which is essential for dorsal development and becomes dorsally enriched shortly after cortical rotation. In mammalian cells cytoplasmic accumulation of beta-catenin follows reduction of the specific activity of glycogen synthase kinase 3-beta (GSK3beta). In Xenopus embryos, exogenous GSK3beta suppresses dorsal development as predicted and GSK3beta dominant negative (kinase dead) mutants cause ectopic axis formation. However, endogenous GSK3beta regulation is poorly characterized. Two modes of GSK3beta regulation in Xenopus have been demonstrated. Endogenous mechanisms cause depletion of GSK3beta protein on the dorsal side of the embryo. The timing, location and magnitude of the depletion correspond to those of endogenous beta-catenin accumulation. UV and D2O treatments that abolish and enhance dorsal character of the embryo, respectively, correspondingly abolish and enhance GSK3beta depletion. GSK3-binding protein (GBP), a candidate regulator of GSK3beta, is known to be essential for axis formation, and it also induces depletion of GSK3beta. Depletion of GSK3beta is a previously undescribed mode of regulation of this signal transducer. The other mode of regulation is observed in response to Wnt and Dishevelled expression. Neither Wnt nor Dishevelled causes depletion but instead they reduce GSK3beta-specific activity. Thus, Wnt/Dsh and GBP appear to effect two biochemically distinct modes of GSK3beta regulation (Dominguez, 2000).

GBP’s action is mechanistically distinct from the actions of Wnt and dishevelled signaling. Specifically, GBP causes GSK3beta to disappear while Wnt and Dishevelled signaling do not. Conversely, Wnt and Dsh both alter specific activity of GSK3beta, though there may be circumstances in which Wnt does not reduce GSK3beta kinase activity. The lack of effect on GSK3beta abundance due to Wnt or Dsh suggests that decreased GSK3beta abundance is not a consequence of Wnt or Dishevelled signaling, either directly (e.g. protein modifications reduce both specific activity and stability) or via a feedback mechanism (e.g. beta-catenin signals to destabilize GSK3beta). It is concluded that the dorsal decrease in endogenous GSK3beta protein levels can account for dorsal axis formation without invoking some additional undetected Wnt- or Dishevelled-dependent specific activity change. These results provide direct biochemical evidence that either the Wnt signal transduction pathway is not the endogenous initiator of dorsal axis formation or that endogenous Wnt and Dishevelled signaling is very different from signaling by exogenous Wnt or Dishevelled (Dominguez, 2000).

In Xenopus, axis development is initiated by dorsally elevated levels of cytoplasmic ß-catenin, an intracellular factor regulated by GSK3 kinase activity. Upon fertilization, factors that increase ß-catenin stability are translocated to the prospective dorsal side of the embryo in a microtubule-dependent process. However, neither the identity of these factors nor the mechanism of their movement is understood. The GSK3 inhibitory protein GBP/Frat is shown to bind kinesin light chain (KLC), a component of the microtubule motor kinesin. Upon egg activation, GBP-GFP and KLC-GFP form particles and exhibit directed translocation. KLC, through a previously uncharacterized conserved domain, binds a region of GBP that is required for GBP translocation and for GSK3 binding, and competes with GSK3 for GBP. A model is proposed in which conventional kinesin transports a GBP-containing complex to the future dorsal side, where GBP dissociates and contributes to the local stabilization of ß-catenin by binding and inhibiting GSK3 (Weaver, 2003).

The formation of the dorsoanterior axis in Xenopus is dependent upon a series of events that occur during the first cell cycle after fertilization. Sperm entry initiates a rotation of the peripheral layer of the egg, called the cortex, relative to the inner core cytoplasm. This event, called cortical rotation, results in a 30° displacement of the vegetal cortex toward the future dorsoanterior region. Cortical rotation coincides with the translocation of a 'dorsalizing activity' that also moves from the vegetal pole up toward the prospective dorsal side of the embryo. Translocation of the dorsalizing activity is both necessary and sufficient for the formation of the Spemann organizer, which regulates the formation of the embryonic axes during the gastrula stages (Weaver, 2003 and references therein).

Although the molecular identity of the dorsal determinants is not clear, it is known that their translocation leads to the dorsal accumulation of ß-catenin, which then activates the expression of dorsal organizer genes at the onset of zygotic transcription. Cytoplasmic transplant experiments using ß-catenin-depleted embryos have shown that ß-catenin is not the endogenous dorsalizing activity, but that instead this activity probably consists of proteins involved in ß-catenin stabilization. ß-catenin is normally phosphorylated by the serine-threonine kinase glycogen synthase kinase 3 (GSK3) within a protein complex that also includes Axin and the adenomatous polyposis coli gene product (APC), and this phosphorylation targets ß-catenin for degradation by the ubiquitin-proteosome pathway. Work from many laboratories has led to a model in which the localized inhibition of GSK3 in the dorsal region causes the dorsal accumulation of ß-catenin. How GSK3 becomes locally inhibited by the dorsal determinants, however, is still an open question (Weaver, 2003).

A strong candidate component of the translocating dorsalizing activity is GBP, a vertebrate-specific GSK3-binding protein. Depletion of endogenous GBP from the embryo with antisense oligonucleotides causes a loss of dorsal axial structures, showing that GBP is required for dorsal axis formation. GBP inhibits GSK3 activity by preventing its binding to Axin, thus preventing GSK3 from phosphorylating ß-catenin. When microinjected ventrally, GBP mimics the endogenous dorsal signal and induces the formation of a secondary dorsal axis, and overexpression of GBP also leads to GSK3 degradation in the cortical shear zone. In addition to binding GSK3, GBP also binds directly to Dsh, a positive effector of the canonical Wnt signaling pathway. Together, these two proteins potently synergize to stabilize ß-catenin (Weaver, 2003).

Thus, both GBP and its binding partner Dsh have characteristics that strongly suggest that they are part of the endogenous dorsalizing activity. Furthermore, Dsh-GFP has been shown to form particles in the shear zone that exhibit directed movement on microtubules, and endogenous Dsh accumulates dorsally by the end of cortical rotation. However, no direct molecular link has yet been established between either GBP or Dsh and the microtubule array. In this study, it has been demonstrated that GBP binds kinesin light chain (KLC), a component of the plus end-directed microtubule motor kinesin. Like Dsh, GBP-GFP and KLC-GFP form particles that exhibit fast, directional translocation in the shear zone during the period of cortical rotation. These results suggest a model in which GBP acts initially as a link between the transport apparatus and the dorsalizing activity, and subsequently as an inhibitor of GSK3 in the ß-catenin degradation complex (Weaver, 2003).

XsalF, a frog homolog of the Drosophila homeotic selector Spalt, plays an essential role for the forebrain/midbrain determination in Xenopus. XsalF overexpression expands the domain of forebrain/midbrain genes and suppresses midbrain/hindbrain boundary (MHB) markers and anterior hindbrain genes. Loss-of-function studies show that XsalF is essential for the expression of the forebrain/midbrain genes and for the repression of the caudal genes. Interestingly, XsalF functions by antagonizing canonical Wnt signaling, which promotes caudalization of neural tissues. XsalF is required for anterior-specific expressions of GSK3ß and Tcf3, genes encoding antagonistic effectors of Wnt signaling. Loss-of-function phenotypes of GSK3ß and Tcf3 mimic those of XsalF while injections of GSK3ß and Tcf3 rescue loss-of-function phenotypes of XsalF. These findings suggest that the forebrain/midbrain-specific gene XsalF negatively controls cellular responsiveness to posteriorizing Wnt signals by regulating region-specific GSK3ß and Tcf3 expression (Onai, 2004).

The tumor suppressor Smad4/DPC4 is regulated by phosphorylations that integrate FGF, Wnt, and TGF-beta signaling

Smad4 (see Drosophila Medea) is a major tumor suppressor currently thought to function constitutively in the transforming growth factor beta (TGF-beta)-signaling pathway. This study reports that Smad4 activity is directly regulated by the Wnt and fibroblast growth factor (FGF) pathways through GSK3 and mitogen-activated protein kinase (MAPK; see Drosophila Rolled) phosphorylation sites. FGF activates MAPK, which primes three sequential GSK3 phosphorylations that generate a Wnt-regulated phosphodegron bound by the ubiquitin E3 ligase beta-TrCP (see Drosophila Slmb). In the presence of FGF, Wnt potentiates TGF-beta signaling by preventing Smad4 GSK3 phosphorylations that inhibit a transcriptional activation domain located in the linker region. When MAPK is not activated, the Wnt and TGF-beta signaling pathways remain insulated from each other. In Xenopus embryos, these Smad4 phosphorylations regulate germ-layer specification and Spemann organizer formation. The results show that three major signaling pathways critical in development and cancer are integrated at the level of Smad4 (Demagny, 2014: PubMed).

Effects of canonical Wnt signaling on dorso-ventral specification of the mouse telencephalon: inactivation of β-catenin

Wnt signaling is involved in numerous processes during vertebrate CNS development. In this study, conditional Cre/loxP system was used in the mouse to ablate or activate ß-catenin in the telencephalon in two time windows: before and after the onset of neurogenesis. Β-catenin mediated Wnt signals are required to maintain the molecular identity of the pallium. Inactivation of β-catenin in the telencephalon before neurogenesis results in downregulated expression of dorsal markers Emx1, Emx2 and Ngn2, and in ectopic up-regulation of ventral markers Gsh2, Mash1 and Dlx2 in the pallium. In contrast, ablation of ß-catenin after the onset of cortical neurogenesis (E11.5) does not result in a dorso-ventral fate shift. In addition, activation of canonical Wnt signaling in the subpallium leads to a repression of ventral telencephalic cell identities as shown by the down-regulation of subpallial markers Dlx2, Nkx2.1, Gsh2, Olig2 and Mash1. This was accompanied with an expansion of dorsal identities ventrally as shown by the expanded expression domains of pallial markers Pax6 and Ngn2. Thus, the data suggest that canonical Wnt signals are involved in maintaining the identity of the pallium by controlling expression of dorsal markers and by suppressing ventral programs from being activated in pallial progenitor cells (Backman, 2004).

Signaling downstream of mammalian GSK-3

A mammalian homolog of Drosophila Shaggy (rat GSK3 beta), found during vertebrate embryogenesis, was overexpressed in Xenopus embryos in order to study the role of glycogen synthase kinase 3 beta (GSK3 beta). Microinjection of rat GSK3 beta mRNA into animal ventral blastomeres of 8-cell-stage embryos triggers development of ectopic cement glands with an adjacent anterior neural tissue as evidenced by in situ hybridization with Xotx2 (Drosophila homolog: Orthodenticle), a fore/midbrain marker, and NCAM, a pan-neural marker. In contrast, animal dorsal injection of the same dose of GSK3 beta mRNA causes eye deficiencies, whereas vegetal injections have no pronounced effects on normal development. The observed phenotypes are dose-dependent and tightly correlate with GSK3 beta enzymatic activity. Lineage tracing experiments show that the effects of GSK3 beta are cell autonomous and that ectopic cement glands and eye deficiencies arise directly from cells containing GSK3 beta mRNA. Molecular marker analysis of ectodermal explants overexpressing GSK3 beta reveals activation of Xotx2 and of cement gland marker XAG-1, but expression of NCAM and XIF-3 is not detected. The phenotypic effects of mRNA encoding a Xenopus homolog of GSK3 beta are identical to those of rat GSK3 beta mRNA. It is hypothesized that GSK3 beta mediates the initial steps of neural tissue specification and modulates anteroposterior ectodermal patterning via activation of Otx2 transcription. These observations implicate GSK3 beta in signaling pathways operating during neural tissue development and during specification of anterior ectodermal cell fates (Itoh, 1995).

In mammals phosphorylation mediated by Glycogen synthase kinase 3 (GSK-3) is involved in negative regulation of c-Jun DNA-binding function in vitro. Two forms of GSK-3 function to decrease the DNA-binding activity as well as the transcriptional activation elicited by c-Jun in vivo. Similarly, other members of the jun family (JunB, JunD and v-Jun) are negatively regulated by GSK-3 in vivo, although to a slightly lesser extent than c-Jun. The products of the sgg gene can also function in mammals as negative regulators of Jun/AP (de Groot, 1993).

The dishevelled (dsh) gene family encodes cytoplasmic proteins that have been implicated in Wnt/Wingless (Wg) signaling. To demonstrate functional conservation of Dsh family proteins, two mouse homologs of Drosophila Dsh, Dvl-1 and Dvl-2, were biochemically characterized in mouse and Drosophila cell culture systems. Treatment with a soluble Wnt-3A leads to hyperphosphorylation of Dvl proteins and a concomitant elevation of the cytoplasmic beta-catenin levels in mouse NIH3T3, L, and C57MG cells. This coincides well with the finding in a Drosophila wing disc cell line, clone-8, that Wg treatment induces hyperphosphorylation of Dsh. Furthermore, mouse Dvl proteins affect downstream components of Drosophila Wg signaling as does Dsh; overexpression of Dvl proteins in clone-8 cells results in elevation of Armadillo (Drosophila homolog of beta-catenin) and Drosophila E-cadherin levels; hyperphosphorylation of Dvl proteins themselves, and inhibition of Zeste-White3 kinase-mediated phosphorylation of a microtubule-binding protein, Tau. In addition, casein kinase II coimmunoprecipitates with Dvl proteins, and Dvl proteins are phosphorylated in these immune complexes. These results are direct evidence that Dsh family proteins mediate a set of conserved biochemical processes in the Wnt/Wg signaling pathway (Lee, 1999).

Dvl-1 or Dvl-2 overexpression elevates the Arm protein levels. The epistatic analysis of the Wg pathway suggests that overexpressed Dvl-1 or Dvl-2 inhibits ZW3, which in turn causes the Arm protein level to elevate. To directly evaluate Dsh-, Dvl-1-, or Dvl-2-induced modulation of ZW3 activities, an in vivo assay for GSK-3beta was developed that uses the microtubule-binding protein, Tau, which is another good substrate for GSK-3beta since Drosophila ZW3 has been shown to be replaceable with rat GSK-3beta. With the anti-Tau antibody that recognizes all forms of Tau, the transfected Tau protein is detected as an apparently broad band, which actually consists of several species of Tau that have different mobilities. Endogenous ZW3 kinase activity in clone-8 cells is too low to produce detectable amounts of phosphorylated Tau. Co-transfection of ZW3 with Tau induces the phosphorylation of Tau in clone-8 cells. However, despite the expression of the same amount of Tau and ZW3 protein, no phosphorylated form of Tau is detectable in Clone-8/Dsh, Clone-8/Dvl-1, and Clone-8/Dvl-2 cells, indicating that overexpressed Dsh, Dvl-1, or Dvl-2 inhibits ZW3-mediated phosphorylation of Tau. The simplest explanation for this is that overexpressed Dsh, Dvl-1, or Dvl-2 inhibit ZW3 kinase activity by an unknown mechanism, although the possibility cannot be excluded that Dsh or Dvl overexpression activates phosphatase(s) antagonizing ZW3-mediated phosphorylation of Tau. Probably similar molecular mechanisms of ZW3/GSK-3 suppression are operative in cells stimulated with Wg/Wnt treatment and with Dsh/Dvl overexpression (Lee, 1999).

Glycogen synthase kinase-3 (GSK-3)-alpha and -beta are closely related protein-serine kinases, which act as inhibitory components of Wnt signaling during embryonic development and cell proliferation in adult tissues. Disruption of the murine GSK-3beta gene results in embryonic lethality caused by severe liver degeneration during mid-gestation, a phenotype consistent with excessive tumor necrosis factor (TNF) toxicity, as observed in mice lacking genes involved in the activation of the transcription factor NF-kappaB. GSK-3beta-deficient embryos are rescued by inhibition of TNF using an anti-TNF-alpha antibody. Fibroblasts from GSK-3beta-deficient embryos are hypersensitive to TNF-alpha and show reduced NF-kappaB function. Lithium treatment (which inhibits GSK-3) sensitizes wild-type fibroblasts to TNF and inhibits transactivation of NF-kappaB. The early steps leading to NF-kappaB activation (degradation of I-kappaB and translocation of NF-kappaB to the nucleus) are unaffected by the loss of GSK-3beta, indicating that NF-kappaB is regulated by GSK-3beta at the level of the transcriptional complex. Thus, GSK-3beta facilitates NF-kappaB function (Hoeflich, 2000).


Table of contents


shaggy: Biological Overview | Regulation | Developmental Biology | Effects of Mutation | References

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