Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.26 (GSK)
 6,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Beta-catenin, a member of the Armadillo repeat protein family, binds directly to the cytoplasmic domain of E-cadherin, linking it via alpha-catenin to the actin cytoskeleton. A 30-amino acid region within the cytoplasmic domain of E-cadherin, conserved among all classical cadherins, has been shown to be essential for beta-catenin binding. This region harbors several putative casein kinase II (CKII) and glycogen synthase kinase-3beta (GSK-3beta) phosphorylation sites and is highly phosphorylated. Here we report that in vitro this region is indeed phosphorylated by CKII and GSK-3beta, which results in an increased binding of beta-catenin to E-cadherin. Additionally, in mouse NIH3T3 fibroblasts expression of E-cadherin with mutations in putative CKII sites resulted in reduced cell-cell contacts. Thus, phosphorylation of the E-cadherin cytoplasmic domain by CKII and GSK-3beta appears to modulate the affinity between beta-catenin and E-cadherin, ultimately modifying the strength of cell-cell adhesion.
 ...
PMID:Casein kinase II phosphorylation of E-cadherin increases E-cadherin/beta-catenin interaction and strengthens cell-cell adhesion. 1067 52

We screened 90 cases of gastric carcinoma (GCA) samples for beta-catenin exon 3 mutation and assessed its possible relationship with microsatellite instability (MSI). Three mutations were detected in two samples, including a single mutation in an intestinal type and double mutations in a diffuse type GCA. One of the mutations found in the diffuse type GCA sample was a non-sense mutation at codon 68 (CAG-->TAG). This novel mutation was predicted to disrupt the binding of beta-catenin to alpha-catenin and may be related to the diffuse type morphology. The other two mutations were missense mutations involved or related to the GSK-3beta phosphorylation site, which have been reported previously. No MSI can be demonstrated in the two cases with beta-catenin mutation. Our results suggested that beta-catenin mutation was infrequent in GCA and appeared not specific for MSI.
 ...
PMID:Somatic beta-catenin mutation in gastric carcinoma--an infrequent event that is not specific for microsatellite instability. 1116 16

beta-Catenin is a multi-functional cellular component and a substrate for several protein kinases. Here we investigated the interaction of protein kinase CKII (casein kinase II) and beta-catenin. We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin. In comparing wild-type and Ser/Thr-mutant beta-catenin, a decreased affinity of the mutant protein to alpha-catenin was observed. Moreover, kinase assays in vitro demonstrate a CKII-dependent increase in the binding of wild-type beta-catenin with alpha-catenin. In line with that, cells expressing Ser/Thr-mutant beta-catenin exhibit an increased migratory potential, which correlates with an enhanced cytosolic localization and a reduced association with the cytoskeleton of the mutant protein. From these results we conclude that CKII regulates the function of beta-catenin in the cadherin adhesion complex as well as its cytoplasmic stability.
 ...
PMID:Protein kinase CKII regulates the interaction of beta-catenin with alpha-catenin and its protein stability. 1243 63

Alzheimer's disease is associated with increased production and aggregation of amyloid-beta (Abeta) peptides. Abeta peptides are derived from the amyloid precursor protein (APP) by sequential proteolysis, catalysed by the aspartyl protease BACE, followed by presenilin-dependent gamma-secretase cleavage. Presenilin interacts with nicastrin, APH-1 and PEN-2 (ref. 6), all of which are required for gamma-secretase function. Presenilins also interact with alpha-catenin, beta-catenin and glycogen synthase kinase-3beta (GSK-3beta), but a functional role for these proteins in gamma-secretase activity has not been established. Here we show that therapeutic concentrations of lithium, a GSK-3 inhibitor, block the production of Abeta peptides by interfering with APP cleavage at the gamma-secretase step, but do not inhibit Notch processing. Importantly, lithium also blocks the accumulation of Abeta peptides in the brains of mice that overproduce APP. The target of lithium in this setting is GSK-3alpha, which is required for maximal processing of APP. Since GSK-3 also phosphorylates tau protein, the principal component of neurofibrillary tangles, inhibition of GSK-3alpha offers a new approach to reduce the formation of both amyloid plaques and neurofibrillary tangles, two pathological hallmarks of Alzheimer's disease.
 ...
PMID:GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides. 2215 50

We overexpressed two deletion mutants of the N-terminal domain of beta-catenin in ventral optic axons in living Xenopus tadpoles. One deletion mutant contained both the alpha-catenin and the GSK-3beta binding sites of the N-terminal domain of beta-catenin (NTERM), and the second deletion mutant contained only the GSK-3beta binding site (beta-cat107). Expression of NTERM in ventral optic axons dispersed and induced anterior and lateral shifts in their targeting locations in the dorsal tectum. In contrast, beta-cat107 compressed and shifted the synaptic targeting locations of ventral optic axons medially and posteriorly. In addition, NTERM-expressing ventral optic axons formed arbors that were wider than controls whereas beta-cat107 axonal arbors were narrower compared with controls. These data suggest that the interactions of beta-catenin with alpha-catenin and GSK-3beta exert opposing effects on the terminal projections of ventral optic axons.
 ...
PMID:GSK-3beta and alpha-catenin binding regions of beta-catenin exert opposing effects on the terminal ventral optic axonal projection. 1842 51