Protein phosphatase 2A and its B56 regulatory subunit inhibit Wnt signaling in Xenopus

Li, Xinghai; Yost, H. Joseph; Virshup, David M.; Seeling, Joni M.

doi:10.1093/emboj/20.15.4122

Cited by 138 publications

(137 citation statements)

References 54 publications

(84 reference statements)

Supporting

Mentioning

130

Contrasting

Unclassified

Order By: Relevance

“…The role of PP2A, however, remains unclear. Overexpression studies in cultured cells and Xenopus embryos have given conflicting results as to whether PP2A is a positive or negative regulator of the Wnt pathway (Seeling et al, 1999;Ratcliffe et al, 2000;Li et al, 2001). A Drosophila mutant of a B subunit of PP2A has provided support for a positive role for PP2A in the Wnt signaling pathway (i.e.…”

Section: Protein Phosphatase 2amentioning

confidence: 99%

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

2006

View full text Add to dashboard Cite

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.

show abstract

Section: Protein Phosphatase 2amentioning

confidence: 99%

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

2006

View full text Add to dashboard Cite

show abstract

“…In fact, B56g directly interacts with APC in the b-catenin/axin/GSK-3b complex and induces b-catenin inactivation/degradation (Seeling et al, 1999). Moreover, the catalytic subunit of PP2A has been found associated to axin (Li et al, 2001), suggesting that PP2A:B56 is part of the b-catenin degradation complex.…”

Section: Protein Phosphatase 2a (Pp2a) a Phosphatase With Tumour Supmentioning

confidence: 99%

ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia

Perrotti

Neviani

2006

Br J Cancer

View full text Add to dashboard Cite

The deregulated kinase activity of p210-BCR/ABL oncoproteins, hallmark of chronic myelogenous leukaemia (CML), induces and sustains the leukaemic phenotype, and contributes to disease progression. Imatinib mesylate, a BCR/ABL kinase inhibitor, is effective in most of chronic phase CML patients. However, a significant percentage of CML patients develop resistance to imatinib and/or still progresses to blast crisis, a disease stage that is often refractory to imatinib therapy. Furthermore, there is compelling evidence indicating that the CML leukaemia stem cell is also resistant to imatinib. Thus, there is still a need for new drugs that, if combined with imatinib, will decrease the rate of relapse, fully overcome imatinib resistance and prevent blastic transformation of CML. We recently reported that the activity of the tumour suppressor protein phosphatase 2A (PP2A) is markedly inhibited in blast crisis CML patient cells and that molecular or pharmacologic re-activation of PP2A phosphatase led to growth suppression, enhanced apoptosis, impaired clonogenic potential and decreased in vivo leukaemogenesis of imatinib-sensitive and -resistant (T315I included) CML-BC patient cells and/or BCR/ABL þ myeloid progenitor cell lines. Thus, the combination of PP2A phosphatase-activating and BCR/ABL kinase-inhibiting drugs may represent a powerful therapeutic strategy for blast crisis CML patients.

show abstract

“…CKI activates Wnt signaling, phosphorylates multiple components of the ␤-catenin degradation complex, and increases ␤-catenin abundance in in vivo systems (10,11). To test whether CKI can directly increase ␤-catenin abundance, we used an in vitro assay of ␤-catenin degradation in Xenopus egg extracts (7,24). ␤-catenin was degraded in egg extracts with a half-life of less than 1 h (Fig.…”

Section: Direct Interaction Of Cki With Wnt Signaling Componentsmentioning

confidence: 99%

“…CKI and PP2A functions appear to be linked through their association with the ␤-catenin degradation complex (7). The ability of CKI to decrease, and the inhibition of CKI to increase, PP2A association with the ␤-catenin degradation complex suggests that these proteins may be proximate to one another in the Wnt pathway.…”

Section: Epistasis Places Cki Upstream Of the B56 Regulatory Subunit mentioning

confidence: 99%

“…PP2A:B56 is likely to be a component of the ␤-catenin degradation complex because epistasis positions B56 downstream of GSK3␤ and axin but upstream of APC and ␤-catenin, and axin coimmunoprecipitates PP2A:B56, C, and structural A subunits. PP2A C and A also rescue Wnt-induced secondary axes, and PP2A activity is required for ␤-catenin degradation in Xenopus egg extracts (4,7).…”

mentioning

confidence: 95%

See 1 more Smart Citation

Casein kinase I phosphorylates and destabilizes the β-catenin degradation complex

Gao

Seeling

Hill

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

211

214

View full text Add to dashboard Cite

Wnt signaling plays a key role in cell proliferation and development. Recently, casein kinase I (CKI) and protein phosphatase 2A (PP2A) have emerged as positive and negative regulators of the Wnt pathway, respectively. However, it is not clear how these two enzymes with opposing functions regulate Wnt signaling. Here we show that both CKI␦ and CKI interacted directly with Dvl-1, and that CKI phosphorylated multiple components of the Wnt-regulated ␤-catenin degradation complex in vitro, including Dvl-1, adenomatous polyposis coli (APC), axin, and ␤-catenin. Comparison of peptide maps from in vivo and in vitro phosphorylated ␤-catenin and axin suggests that CKI phosphorylates these proteins in vivo as well. CKI abrogated ␤-catenin degradation in Xenopus egg extracts. Notably, CKI decreased, whereas inhibition of CKI increased, the association of PP2A with the ␤-catenin degradation complex in vitro. Additionally, inhibition of CKI in vivo stabilized the ␤-catenin degradation complex, suggesting that CKI actively destabilizes the complex in vivo. The ability of CKI to induce secondary body axes in Xenopus embryos was reduced by the B56 regulatory subunit of PP2A, and kinase-dead CKI acted synergistically with B56 in inhibiting Wnt signaling. The data suggest that CKI phosphorylates and destabilizes the ␤-catenin degradation complex, likely through the dissociation of PP2A, providing a mechanism by which CKI stabilizes ␤-catenin and propagates the Wnt signal.T he Wnt signaling pathway is a critical regulator of embryonic development and cellular proliferation (1, 2). In the absence of Wnt, ␤-catenin is phosphorylated by glycogen synthase kinase 3␤ (GSK3␤) in a complex that also contains adenomatous polyposis coli (APC) and axin, targeting ␤-catenin for ubiquitination and degradation. When Wnt binds to the frizzled receptor, disheveled (Dvl͞Dsh) is hyperphosphorylated and activated. Dvl activation leads to inhibition of GSK3␤, decreased phosphorylation of axin, APC, and ␤-catenin, and stabilization of ␤-catenin. ␤-catenin is then translocated to the nucleus where it binds to Lef͞Tcf proteins and stimulates expression of Wnt-responsive genes.Multiple proteins have recently been identified as regulators of ␤-catenin signaling. Protein phosphatase 2A (PP2A), a heterotrimeric serine͞threonine phosphatase (3), interacts via its B56 regulatory subunit with APC, Dsh, and axin (4-7), whereas its catalytic C subunit interacts with axin (8, 9). Inhibition of PP2A by okadaic acid increases, whereas B56 expression decreases, ␤-catenin abundance in 293 cells. In Xenopus, B56 reduces both Xwnt-8-induced secondary axes and siamois and Xnr-3 expression. PP2A:B56 is likely to be a component of the ␤-catenin degradation complex because epistasis positions B56 downstream of GSK3␤ and axin but upstream of APC and ␤-catenin, and axin coimmunoprecipitates PP2A:B56, C, and structural A subunits. PP2A C and A also rescue Wnt-induced secondary axes, and PP2A activity is required for ␤-catenin degradation in Xenopus egg extracts (4, 7).Recent ...

show abstract

Protein phosphatase 2A and its B56 regulatory subunit inhibit Wnt signaling in Xenopus

Cited by 138 publications

References 54 publications

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

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

ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia

Casein kinase I phosphorylates and destabilizes the β-catenin degradation complex

Contact Info

Product

Resources

About