Disease relevance of sgg

• These data show that tau abnormalities significantly disrupt neuronal function, in a phosphorylation-dependent manner, before the classical pathological hallmarks are evident and also suggest that the inhibition of GSK-3beta might have potential therapeutic benefits in tauopathies [1].
• In both nkd and germ line clone-derived zw3 embryos the pattern elements derived from the anterior-most part of each segment, the denticle belts, are deleted [2].
• We showed that human Tau protein was phosphorylated by endogenous protein kinases in flies, and overexpression of either GSK3beta or Cdk5 enhanced tau-induced toxicity [3].
• The encoded proteins were 70% identical to GSK-3 and sgg over the protein kinase catalytic domain and, after production in Escherichia coli, autophosphorylated mainly on threonine and serine residues, but phosphotyrosine was also detected [4].
• In view of the potential importance of GSK-3 beta in mammalian development and the lack of previous characterisation, we have expressed this protein in insect cells using recombinant baculovirus [5].

Psychiatry related information on sgg

• Tissue-specific overexpression of the glycogen synthase kinase-3 (GSK-3) ortholog shaggy (sgg) shortens the period of the Drosophila circadian locomotor activity cycle [6].

High impact information on sgg

• Ci-155 proteolysis is also inhibited if cells lack activity of the Drosophila GSK3, Shaggy, previously implicated in Wingless signaling [7].
• Our results indicate a role for SGG/GSK-3 in TIMELESS phosphorylation and in the regulated nuclear translocation of the PERIOD/TIMELESS heterodimer [6].
• Genetic epistasis experiments indicate that wg signaling operates by inactivating the zw3 repression of en autoactivation [8].
• Here, we report that the segment polarity gene zeste-white 3 (zw3; also known as shaggy) acts as a repressor of en autoregulation [8].
• Here we show that Sgg is also a negative regulator in the Hedgehog (Hh) pathway [9].

Chemical compound and disease context of sgg

• Effect of lithium on the circadian rhythms of locomotor activity and glycogen synthase kinase-3 protein expression in the mouse suprachiasmatic nuclei [10].

Biological context of sgg

• 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 [9].
• Our double-mutant analysis shows that, in contrast to Zw3, Nkd acts when the Wg pathway is active to restrain signal transduction [11].
• In Drosophila, the GSK-3 homologue is encoded by zw3sgg, a segment-polarity gene involved in embryogenesis that acts downstream of wg [12].
• We demonstrate that elevated levels of zeste white 3 in the ectoderm and mesoderm result in phenotypes that resemble a loss of wingless [13].
• That is, a dominant negative GSK-3beta does not specifically activate Tcf transcription and stimuli (lithium or phytohemagglutinin) that inhibit GSK-3beta activity also do not activate Tcf reporter genes [14].

Anatomical context of sgg

• Using Drosophila cell line assays, we found, in contrast to previous reports, that Wg induces accumulation of its transducer Armadillo (Arm)/beta-catenin without significant alteration of global Sgg-specific activity [15].
• Li+ treatment of Drosophila S2 cells and rat PC12 cells induces accumulation of cytoplasmic Armadillo/beta-catenin, demonstrating that Li+ can mimic Wingless signalling in intact cells, consistent with its inhibition of GSK-3 [12].
• Dual role for the zeste-white3/shaggy-encoded kinase in mesoderm and heart development of Drosophila [16].
• Thus, inhibition of GSK-3beta is insufficient to activate Tcf-dependent transcription in T lymphocytes [14].
• In contrast, in C57MG fibroblast cells, lithium inactivates GSK-3beta and induces Tcf-controlled transcription [14].

Associations of sgg with chemical compounds

• Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells [12].
• The phenotypic consequences of Li+ treatment on Xenopus embryos and sporulating Dictyostelium are similar to the effects of inhibition or disruption, respectively, of a highly conserved protein serine/threonine kinase, glycogen synthase kinase-3 (GSK-3) [12].
• His-tagged Arm was phosphorylated by CKIalpha in vitro on a set of serine and threonine residues that are also phosphorylated by Zeste-white 3 [17].
• Yet Sgg and Dbt often require a phosphoserine in their target site, and analysis of Per phosphorylation in dbt mutants suggests a role for other kinases [18].
• However, unlike MAP kinases, GSK-3 is highly phosphorylated on tyrosine and thus active in resting cells [19].

Enzymatic interactions of sgg

• In agreement with a previous study using human GSK-3beta, Wg did not cause phosphorylation changes of the Ser9 or Tyr214 regulatory phosphorylated sites of Sgg [15].

Regulatory relationships of sgg

• Levels of cytoplasmic Armadillo are also regulated by Zeste-White 3 kinase [20].
• Moreover, sgg could induce the ectopic expression of achaete in anterior clones [21].

Other interactions of sgg

• Although zeste-white3 (Zw3)-mediated Arm phosphorylation has been implicated in its degradation, we have recently shown that casein kinase Ialpha (CKIalpha) also phosphorylates Arm and induces its degradation [22].
• Epistatic genetic studies indicate that Tws functions downstream of Dishevelled and upstream of Sgg and Armadillo [23].
• Drosophila caspase transduces Shaggy/GSK-3beta kinase activity in neural precursor development [24].
• While the activities of dsh, zw3 and arm appear to be specific to the paracrine feedback pathway, the more direct autoregulatory pathway requires porc [25].
• Tcf-1-mediated transcription in T lymphocytes: differential role for glycogen synthase kinase-3 in fibroblasts and T cells [14].

Analytical, diagnostic and therapeutic context of sgg

• Microinjection of the mRNA encoding a catalytically inactive form of rat GSK-3 beta into a ventrovegetal blastomere of eight-cell embryos caused ectopic formation of a secondary body axis containing a complete set of dorsal and anterior structures [26].
• Using immunoprecipitation of endogenous Daxin protein from embryos we show that Daxin interacts with Armadillo and Zeste-white 3 [27].
• We have amplified by PCR Arabidopsis cDNA and genomic sequences related to the product of the shaggy/zeste-white 3 (sgg) segment polarity gene of Drosophila [4].
• Sequence analysis indicates that RIM11 specifies a protein kinase related to rat glycogen synthase kinase 3 and the Drosophila shaggy/zw3 gene product [28].

References