Wingless inactivates glycogen synthase kinase-3 via an intracellular signalling pathway which involves a protein kinase C.

Cook, David P.; Fry, Michael; Hughes, Kenneth; Sumathipala, Rushika N.; Woodgett, James R.; Dale, Trevor C.

doi:10.1002/j.1460-2075.1996.tb00830.x

Cited by 364 publications

(303 citation statements)

References 38 publications

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“…Several signaling pathways, most notably the insulin pathway, inhibit GSK3 by phosphorylating serine 9 (Ser9) on GSK3 (reviewed by Cohen and Frame (2001)). GSK3 activity measured in semi-purified preparations using a peptide substrate is inhibited by insulin signaling very rapidly, with a maximum effect occurring 10 min after stimulation (Cook et al, 1996;Ding et al, 2000). Unlike insulin, however, Wnt signaling does not obviously affect the phosphorylation state of GSK3 (Ding et al, 2000).…”

Section: B-cateninmentioning

confidence: 99%

β-Catenin destruction complex: insights and questions from a structural perspective

2006

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At the heart of the canonical Wnt signaling pathway is the b-catenin destruction complex, which functions in the absence of Wnt signaling to keep the cytosolic and nuclear levels of b-catenin very low by promoting the phosphorylation and ubiquitination of b-catenin. Structural studies, combined with other experimental approaches, have begun to provide important insights into the mechanism of the destruction complex. We suggest a working model for the destruction complex based on the existing structural and experimental data, and focus on the questions that this model and other studies have raised about the function of the complex in both the normal and Wnt-inhibited states.

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Section: B-cateninmentioning

confidence: 99%

β-Catenin destruction complex: insights and questions from a structural perspective

2006

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“…Current model provides that in the absence of Wnt, glycogen synthase kinase-3b (GSK-3b) acts to cause bcatenin to be phosphorylated and that the phosphorylated b-catenin is complexed with b-TrCP and ubiquitinated, leading to the degradation by the proteasome (Aberle et al, 1997;Kitagawa et al, 1999;Winston et al, 1999). In response to Wnt, GSK-3b is inactivated (Cook et al, 1996), resulting in the accumulation of b-catenin. The accumulated bcatenin is translocated into the nucleus and associates with the transcription enhancers of T cell factor/ lymphocyte enhancer binding factor (TCF/LEF) family, and the complex stimulates the expression of genes including c-myc, c-jun, fra-1, and cyclin D1 (Behrens et al, 1996;Molenaar et al, 1996;He et al, 1998;Mann et al, 1999;Tetsu and McCormick, 1999).…”

Section: Introductionmentioning

confidence: 99%

GSK-3β-dependent phosphorylation of adenomatous polyposis coli gene product can be modulated by β-catenin and protein phosphatase 2A complexed with Axin

et al. 2000

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Axin forms a complex with adenomatous polyposis coli gene product (APC), glycogen synthase kinase-3b (GSK3b), and b-catenin through di erent binding sites and downregulates b-catenin. GSK-3b-dependent phosphorylation of APC-(1211-2075) which has the Axin-binding site was facilitated by Axin, but that of APC-(959-1338) which lacks the Axin-binding site was not. Axin-(298-506) or Axin-(298-832), which has the GSK-3b-and bcatenin-but not APC-binding sites, did not enhance GSK-3b-dependent phosphorylation of either APC-(1211-2075) or APC-(959-1338). Furthermore, b-catenin stimulated the phosphorylation of APC-(959-1338) and APC-(1211-2075) by GSK-3b in the presence of Axin. Consistent with these in vitro observations, expression of b-catenin or Axin in COS cells promoted an SDS gel band shift of APC. These results indicate that APC complexed with Axin is e ectively phosphorylated by GSK-3b and that b-catenin may modulate this phosphorylation. In addition, the heterodimeric form of protein phosphatase 2A (PP2A) directly bound to Axin, and PP2A complexed with Axin dephosphorylated APC phosphorylated by GSK-3b. Taken together, these results suggest that GSK-3b-dependent phosphorylation of APC can be modulated by b-catenin and PP2A complexed with Axin. Oncogene (2000) 19, 537 ± 545.

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“…The binding of wnt to its receptor frizzled, results in the inhibition of GSK activity (Cook et al, 1996) and a subsequent elevation in b-catenin level (Papko et al, 1996). This is followed by the translocation of bcatenin into the nucleus and its interaction with LEF/ TCF family transcription factors (Behrens et al, 1996;Huber et al, 1996;Molenaar et al, 1996), leading to the transactivation of LEF/TCF-responsive target genes (Molenaar et al, 1996;van de Wetering et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Differential interaction of plakoglobin and β-catenin with the ubiquitin-proteasome system

et al. 2000

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b-Catenin and plakoglobin are closely related armadillo family proteins with shared and distinct properties; Both are associated with cadherins in actin-containing adherens junctions. Plakoglobin is also found in desmosomes where it anchors intermediate ®laments to the desmosomal plaques. b-Catenin, on the other hand, is a component of the Wnt signaling pathway, which is involved in embryonic morphogenesis and tumorigenesis. A key step in the regulation of this pathway involves modulation of b-catenin stability. A multiprotein complex, regulated by Wnt, directs the phosphorylation of bcatenin and its degradation by the ubiquitin-proteasome system. Plakoglobin can also associate with members of this complex, but inhibition of proteasomal degradation has little e ect on its levels while dramatically increasing the levels of b-catenin. b-TrCP, an F-box protein of the SCF E3 ubiquitin ligase complex, was recently shown to play a role in the turnover of b-catenin. To elucidate the basis for the apparent di erences in the turnover of bcatenin and plakoglobin we compared the handling of these two proteins by the ubiquitin-proteasome system. We show here that a deletion mutant of b-TrCP, lacking the F-box, can stabilize the endogenous b-catenin leading to its nuclear translocation and induction of b-catenin/ LEF-1-directed transcription, without a ecting the levels of plakoglobin. However, when plakoglobin was overexpressed, it readily associated with b-TrCP, e ciently competed with b-catenin for binding to b-TrCP and became polyubiquitinated. Fractionation studies revealed that about 85% of plakoglobin in 293 cells, is Triton X-100-insoluble compared to 50% of b-catenin. These results suggest that while both plakoglobin and b-catenin can comparably interact with b-TrCP and the ubiquitination system, the sequestration of plakoglobin by the membrane-cytoskeleton system renders it inaccessible to the proteolytic machinery and stabilizes it.

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Wingless inactivates glycogen synthase kinase-3 via an intracellular signalling pathway which involves a protein kinase C.

Cited by 364 publications

References 38 publications

β-Catenin destruction complex: insights and questions from a structural perspective

β-Catenin destruction complex: insights and questions from a structural perspective

GSK-3β-dependent phosphorylation of adenomatous polyposis coli gene product can be modulated by β-catenin and protein phosphatase 2A complexed with Axin

Differential interaction of plakoglobin and β-catenin with the ubiquitin-proteasome system

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