Wnt3a-Mediated Formation of Phosphatidylinositol 4,5-Bisphosphate Regulates LRP6 Phosphorylation

Pan, Weijun; Choi, Sun‐Cheol; He, Wei; Qin, Yuqi; Volpicelli‐Daley, Laura A.; Swan, Laura E.; Lucast, Louise; Khoo, Cynthia; Zhang, Xiaowu; Li, Lin; Abrams, Charles S.; Sokol, Sergei Y.; Wu, Dianqing

doi:10.1126/science.1160741

Cited by 185 publications

(252 citation statements)

References 22 publications

Supporting

Mentioning

237

Contrasting

Unclassified

Order By: Relevance

“…In this study, we report that regulation of PI4KIIa expression can markedly influence the autophosphorylation of HER-2 at Tyr1248, which may impact members of the signaling pathway downstream of HER-2, such as PI3K and ERK, therefore contributing to the accumulation of HIF-1a, a very important molecule for tumor-induced angiogenesis ( Figure 5). It was also interesting to discover that the effect of PI4KIIa on HIF-1a is subtype specific and kinase activity dependent (Figure 4), similar to the effects of PI4KIIa on the Wnt signaling pathway and on adaptor complex-1 and adaptor complex-3 functions (Wang et al, 2003;Craige et al, 2008;Pan et al, 2008). Although we are still not clear about the detailed mechanism, we hypothesize that the effect of PI4KIIa on the HER-2 signal transduction cascade may Figure 6 A model for the mechanism of PI4KIIa action in tumor growth.…”

Section: Discussionmentioning

confidence: 79%

“…Recent evidence suggests that PI(4)P produced by PI4KIIa has an independent function in its own right beyond that of generally providing a substrate for PI3K. It has been reported that PI4KIIa is important for Wnt signaling in Xenopus embryos and interacts with Dvl (Pan et al, 2008;Qin et al, 2009). Waugh et al (2003) reported that PI4KIIa colocalized with valosincontaining protein, a potential prognostic marker for cancer.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

PI4KIIα is a novel regulator of tumor growth by its action on angiogenesis and HIF-1α regulation

Zhang

et al. 2010

Oncogene

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

PI4KIIα is a novel regulator of tumor growth by its action on angiogenesis and HIF-1α regulation

Zhang

et al. 2010

Oncogene

View full text Add to dashboard Cite

“…PI4K, together with PIP5K, rapidly produces PIP 2 after Wnt stimulation and enhances the phosphorylation of LRP5/6 and oligomerization of Dishevelled and LRP5/6 (Pan et al, 2008). Proteomic analysis also showed that Dishevelled interacts with PI4K, Rho, and even G α13 , after Wnt stimulation (Yokoyama, 2012).…”

Section: Resultsmentioning

confidence: 95%

Leucine-Rich Repeat-Containing G-Protein Coupled Receptor 5/GPR49 Activates G12/13-Rho GTPase Pathway

Kwon

Park

Kim

et al. 2013

Molecules and Cells

View full text Add to dashboard Cite

Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5/GPR49) is highly expressed in adult stem cells of various tissues, such as intestine, hair follicles, and stomach.LGR5 is also overexpressed in some colon and ovarian tumors. Recent reports show that R-spondin (RSPO) family ligands bind to and activate LGR5, enhancing canonical Wnt signaling via the interaction with LRP5/6 and Frizzled. The identity of heterotrimeric G-proteins coupled to LGR5, however, remains unclear. Here, we show that Rho GTPase is a downstream target of LGR5. Overexpression of LGR5 induced SRF-RE luciferase activity, a reporter of Rho signaling. RSPOs, ligands for LGR4, LGR5, and LGR6, however, did not induce SRF-RE reporter activity in the presence of LGR5. Consistently, LGR5-induced activity of the SRF-RE reporter was inhibited by Rho inhibitor C3 transferase and RhoA N19 mutant, and knockdown of Gα 12/13 genes blocked the reporter activity induced by LGR5. In addition, focal adhesion kinase, NF-κB and c-fos, targets of Rho GTPase, were shown to be regulated by LGR5. Here, we have demonstrated, for the first time, that LGR5 is coupled to the Rho pathway through G 12/13 signaling.

show abstract

“…Two lipid kinases, phosphatidylinositol 4-kinase type II (PI4KIIa) and phosphatidylinositol-4-phosphate 5-kinase type I (PIP5KI), which are bound and activated by DVL, mediate Wnt-induced PIP2 ( phosphatidylinositol 4,5-bisphosphate) production that promotes LRP6 phosphorylation by GSK3 and CK1 (Pan et al 2008;Qin et al 2009). One model suggests that PIP2 enhances LRP6 aggregation/signalosome formation (see below) and thereby phosphorylation (Pan et al 2008).…”

Section: Lrp6 Phosphorylation: Roles Of Pip2 G-protein and Other Kimentioning

confidence: 99%

“…One model suggests that PIP2 enhances LRP6 aggregation/signalosome formation (see below) and thereby phosphorylation (Pan et al 2008). An alternative mechanism has been suggested by a study of WTX/ Amer1, which is an X-linked tumor suppressor in Wilms tumor.…”

Section: Lrp6 Phosphorylation: Roles Of Pip2 G-protein and Other Kimentioning

confidence: 99%

Frizzled and LRP5/6 Receptors for Wnt/ -Catenin Signaling

MacDonald

2012

Cold Spring Harbor Perspectives in Biology

508

411

View full text Add to dashboard Cite

Frizzled and LRP5/6 are Wnt receptors that upon activation lead to stabilization of cytoplasmic b-catenin. In this study, we review the current knowledge of these two families of receptors, including their structures and interactions with Wnt proteins, and signaling mechanisms from receptor activation to the engagement of intracellular partners Dishevelled and Axin, and finally to the inhibition of b-catenin phosphorylation and ensuing b-catenin stabilization.T he Wnt/b-catenin pathway, or canonical Wnt pathway as it is often referred to, is an ancient and conserved signaling cascade involving b-catenin acting as a transcriptional coactivator (Logan and Nusse 2004). The pathway is best understood when considered in a two-state model of OFF (without Wnt) and ON (with Wnt). In the OFF state, cytoplasmic b-catenin is constitutively targeted for degradation by two multidomain scaffolding proteins, Axin and Adenomatous polyposis coli (APC), which facilitate the amino-terminal phosphorylation of b-catenin via the kinases GSK3 and CKIa. Phosphorylated b-catenin is recognized by the E3 ubiquitin ligase b-Trcp and is thus ubiquitinated and degraded by the proteasome, thereby maintaining low levels of free b-catenin in the cytoplasm and nucleus (MacDonald et al. 2009). In the ON state, a Wnt ligand binds to the seven-pass transmembrane receptor Frizzled (FZD) and the single-pass low-density lipoprotein receptor-related protein 5 or 6 (LRP5/6) ). The Wnt-FZD -LRP5/6 trimeric complex recruits Dishevelled (DVL) and Axin through the intracellular domains of FZD and LRP5/6, resulting in inhibition of b-catenin phosphorylation and thus ensuing b-catenin stabilization. The rise of cytoplasmic and nuclear levels of b-catenin levels promotes b-catenin partnering with the TCF/ LEF transcription factors for activation of Wntresponsive gene expression.Wnt/b-catenin signaling controls cell proliferation and differentiation and is a key regulatory mechanism for stem cells. As such, mutations in the Wnt pathway cause many diseases including cancer (Clevers 2006). All of the above "core" Wnt/b-catenin signaling components are present in vertebrates and the well-studied fruit fly Drosophila and are also encoded in sequenced genomes of radial symmetric Cnidarians Hydra magnipapillata and Nematostella vectensis (Guder et al. 2006) and of the primitive metazoan sponge Amphimedon queenslandica

show abstract

Wnt3a-Mediated Formation of Phosphatidylinositol 4,5-Bisphosphate Regulates LRP6 Phosphorylation

Cited by 185 publications

References 22 publications

PI4KIIα is a novel regulator of tumor growth by its action on angiogenesis and HIF-1α regulation

PI4KIIα is a novel regulator of tumor growth by its action on angiogenesis and HIF-1α regulation

Leucine-Rich Repeat-Containing G-Protein Coupled Receptor 5/GPR49 Activates G12/13-Rho GTPase Pathway

Frizzled and LRP5/6 Receptors for Wnt/ -Catenin Signaling

Contact Info

Product

Resources

About