Application of an integrated physical and functional screening approach to identify inhibitors of the Wnt pathway

Miller, Bryan W.; Lau, Garnet; Grouios, Chris; Mollica, Emanuela; Barrios‐Rodiles, Miriam; Liu, Yongmei; Datti, Alessandro; Morris, Quaid; Wrana, Jeffrey L.; Attisano, Liliana

doi:10.1038/msb.2009.72

Cited by 45 publications

(55 citation statements)

References 48 publications

(103 reference statements)

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“…A more direct connection was suggested from high-throughput screening analysis of the Wnt pathway, which uncovered TAZ as a potential regulator of Wnt signaling (Miller et al, 2009). TAZ indeed was found to regulate Wnt signals, functioning to inhibit signaling via direct interaction with DVL proteins (Varelas et al, 2010a).…”

Section: Hippo and Wntmentioning

confidence: 99%

Integrating developmental signals: a Hippo in the (path)way

2011

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The Hippo pathway, a signaling cascade that controls cell cycle progression, apoptosis and cell differentiation, has emerged as a fundamental regulator of many physiological and pathological processes. Recent studies have revealed a complex network of interactions directing Hippo pathway activity, and have connected this pathway with other key signaling pathways. Such crosstalk has uncovered novel roles for Hippo signaling, including regulation of TGFb/SMAD and WNT/b-catenin pathways. This review highlights some of the recent findings in the Hippo field with an emphasis on how the Hippo pathway is integrated with other pathways to mediate diverse processes.

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Section: Hippo and Wntmentioning

confidence: 99%

Integrating developmental signals: a Hippo in the (path)way

2011

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“…For example, Wnt ligands can be classified into acting canonically or non-canonically by whether they induce secondary axis formation upon injection into Xenopus embryos. Conventional descriptions of canonical Wnt signaling imply that the pathway is relatively linear -although evidence of more complex interactions has been widely appreciated through proteomic analyses 7,8 . Adherent cells contain relatively large amounts of β-catenin with the vast majority of this lining the plasma membrane in association with cadherin family cell adhesion molecules.…”

Section: Confusing Wnt Terminologymentioning

confidence: 99%

When pathways collide: collaboration and connivance among signalling proteins in development

McNeill

Woodgett

2010

Nat Rev Mol Cell Biol

143

106

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Signal transduction pathways interact at various levels in defining tissue morphology, size and differentiation during development. Understanding of the mechanisms by which these pathways collude has been greatly enhanced by recent insights into how shared components are independently regulated and how the activity of one system is contextualized by others. Traditionally, the components of signalling pathways have been assumed to show pathway fidelity and to act with a high degree of autonomy. However, as illustrated by the Wnt and Hippo pathways, there is increasing evidence that components are often shared between multiple pathways and other components talk to each other through multiple mechanisms.

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“…The LUMIER assay (10,29) allowed us to test a total of 2052 potential interactions with endoglin, ACVRL1 and TGFBR2 receptors. We identified 191 interactions that passed our stringent criteria, with 181 representing potential novel interactions that may define endothelium-specific and HHT-related effector networks.…”

Section: Discussionmentioning

confidence: 99%

“…However, ARL4D, PREB, EIF2AK4, RALGPS2, WDR13, and importantly, PPP2R2B, did not bind to ACVR1 or BMPR1B in the previous study, highlighting the specificity of the interactions detected by LUMIER. Furthermore, these 13 proteins also displayed differential interactions when tested against core members of the Wnt pathway (29), although there were no receptors in the set of baits used in the Wnt pathway LUMIER screens.…”

Section: Identification Of Proteins Interacting With Acvrl1 Endoglinmentioning

confidence: 99%

Novel Protein Interactions with Endoglin and Activin Receptor-like Kinase 1: Potential Role in Vascular Networks

Barrios‐Rodiles

Jerkić

et al. 2014

Molecular & Cellular Proteomics

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Endoglin and activin receptor-like kinase 1 are specialized transforming growth factor-beta (TGF-␤) superfamily receptors, primarily expressed in endothelial cells. Mutations in the corresponding ENG or ACVRL1 genes lead to hereditary hemorrhagic telangiectasia (HHT1 and HHT2 respectively). To discover proteins interacting with endoglin, ACVRL1 and TGF-␤ receptor type 2 and involved in TGF-␤ signaling, we applied LUMIER, a high-throughput mammalian interactome mapping technology. Using stringent criteria, we identified 181 novel unique and shared interactions with ACVRL1, TGF-␤ receptor type 2, and endoglin, defining potential novel important vascular networks. In particular, the regulatory subunit B-beta of the protein phosphatase PP2A (PPP2R2B) interacted with all three receptors. Interestingly, the PPP2R2B gene lies in an interval in linkage disequilibrium with HHT3, for which the gene remains unidentified. We show that PPP2R2B protein interacts with the ACVRL1/TGFBR2/endoglin complex and recruits PP2A to nitric oxide synthase 3 (NOS3). Endoglin overexpression in endothelial cells inhibits the association of PPP2R2B with NOS3, whereas endoglin-deficient cells show enhanced PP2A-NOS3 interaction and lower levels of endogenous NOS3 Serine 1177 phosphorylation. Our data suggest that endoglin regulates NOS3 activation status by regulating PPP2R2B access to NOS3, and that PPP2R2B might be the HHT3 gene. Furthermore, endoglin and ACVRL1 contribute to several novel networks, including TGF-␤ dependent and independent ones, critical for vascular function and potentially defective in HHT. Molecular & Cellular Proteomics 13: 10.1074/mcp.M113.033464, 489-502, 2014. Transforming growth factor-␤ (TGF-␤)1 superfamily ligands, including TGF-␤s, activins and bone morphogenic proteins (BMPs), regulate several pathways essential for vascular development and function (1). Responses to these ligands are controlled by type I and II serine kinase receptors, coreceptors and signaling SMAD intermediates. Endothelial cells express the coreceptor, endoglin, and the specialized type I receptor, ACVRL1 (activin receptor-like kinase 1 or ALK1); both molecules are critical for regulation of angiogenesis and vasomotor function by TGF-␤ superfamily ligands (2, 3).Mutations in ENG and ACVRL1 genes lead to hereditary hemorrhagic telangiectasia (HHT), types 1 and 2, respectively (4). HHT affects 1 in 5000 -8000 people worldwide and is characterized by arteriovenous malformations (AVMs) in mul-

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Application of an integrated physical and functional screening approach to identify inhibitors of the Wnt pathway

Cited by 45 publications

References 48 publications

Integrating developmental signals: a Hippo in the (path)way

Integrating developmental signals: a Hippo in the (path)way

When pathways collide: collaboration and connivance among signalling proteins in development

Novel Protein Interactions with Endoglin and Activin Receptor-like Kinase 1: Potential Role in Vascular Networks

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