Article
Multidisciplinary Sciences
Naotaka Tsutsumi, Sunhee Hwang, Deepa Waghray, Simon Hansen, Kevin M. Jude, Nan Wang, Yi Miao, Caleb R. Glassman, Nathanael A. Caveney, Claudia Y. Janda, Rami N. Hannoush, K. Christopher Garcia
Summary: Wnt morphogens play critical roles in embryonic development and tissue regeneration. They initiate β-catenin signaling by forming ternary receptor complexes composed of tissue-specific Frizzled receptors and shared LRP5/6 coreceptors. The cryo-EM structure of an affinity-matured XWnt8-Frizzled8-LRP6 complex reveals the mechanism of coreceptor discrimination by canonical Wnts through their N termini and linker domains. Chimeric Wnts with modular linker grafts transfer LRP6 domain specificity and enable non-canonical Wnt5a to signal through the canonical pathway.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biochemistry & Molecular Biology
Mingyi Li, Jing Zheng, Dong Luo, Kai Xu, Ren Sheng, Bryan T. MacDonald, Xi He, Xinjun Zhang
Summary: The membrane-tethered protease Tiki inhibits Wnt signaling by cleaving and inactivating Wnt3a. It requires Frizzled (FZD) receptors to antagonize Wnt signaling at the cell surface. Tiki cleaves the N-terminus of Wnt3a or Wnt5a in the Wnt-FZD complex, preventing the recruitment and activation of coreceptors.
Article
Multidisciplinary Sciences
Victoria H. Ng, Zachary Spencer, Leif R. Neitzel, Anmada Nayak, Matthew A. Loberg, Chen Shen, Sara N. Kassel, Heather K. Kroh, Zhenyi An, Christin C. Anthony, Jamal M. Bryant, Amanda Lawson, Lily Goldsmith, Hassina Benchabane, Amanda G. Hansen, Jingjing Li, Starina D'Souza, Andres M. Lebensohn, Rajat Rohatgi, William A. Weiss, Vivian L. Weiss, Charles Williams, Charles C. Hong, David J. Robbins, Yashi Ahmed, Ethan Lee
Summary: The study identifies the USP46 deubiquitylase complex as a positive regulator of Wnt signaling in various organisms. The complex inhibits the degradation of cell surface LRP6, thereby enhancing Wnt signaling. The authors propose a model for the assembly of the complex and its role in Wnt signaling.
NATURE COMMUNICATIONS
(2023)
Article
Immunology
Jian Chen, Jia Liu, Shimin Chen, Ruijun Lai, Chuanchuan Zheng, Jialiang Lu, Xinshao Jiang, Feng He, Chengliang Yang, Kai Li, Kegong Xie, Yujin Tang, Liqiang Wang
Summary: Salinomycin may be a promising therapeutic drug for osteoarthritis (OA) as it has shown protective effects on cartilage cells, reduces disease-associated changes, and delays cartilage destruction and osteophyte formation. Its mechanism of action may involve regulating cell synthesis and inhibiting degradation.
INTERNATIONAL IMMUNOPHARMACOLOGY
(2022)
Article
Geriatrics & Gerontology
Lizbeth Garcia-Velazquez, Paulina Lopez-Carrasco, Clorinda Arias
Summary: This study analyzed the expression levels and protein content of different molecules of the Wnt pathway in different brain regions, and discussed their correlation with changes in synaptic number and morphology. It was found that the downregulation of the Wnt pathway in the aged brain is not associated with changes in the number and structure of central synapses.
EXPERIMENTAL GERONTOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Erin A. Nekritz, Ruth Rodriguez-Barrueco, Koon-Kiu Yan, Meredith L. Davis, Rachel L. Werner, Laura Devis-Jauregui, Partha Mukhopadhyay, Jiyang Yu, David Llobet-Navas, Jose Silva
Summary: The miR-424/503 cluster plays a crucial role in regulating Wnt signaling, MaSC fate, and breast cancer development, with its function involving targeting the LRP6 co-receptor to reduce its expression.
Article
Biochemistry & Molecular Biology
Harminder D. Singh, Jian-xing Ma, Yusuke Takahashi
Summary: By individually knocking out LRP5 and LRP6 in a human retinal pigment epithelium cell line, it was discovered that Wnt ligands can activate Wnt signaling through different co-receptors, indicating differential roles of LRP5 and LRP6 in Wnt signaling regulation.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2021)
Article
Cell Biology
Huifang Zhu, Zijie Su, Jiong Ning, Liang Zhou, Lifeng Tan, Sapna Sayed, Jiaxing Song, Zhongyuan Wang, Huan Li, Qi Sun, Shanshan Liu, Ou Sha, Feng Leng, Xianxiong Chen, Desheng Lu
Summary: TMEM97 upregulation is associated with poor outcome in multiple human cancers, including breast cancer, by enhancing LRP6-mediated Wnt signaling. TMEM97 interacts with LRP6 to promote CK1 delta/epsilon-dependent phosphorylation of LRP6, leading to stabilization of beta-catenin. In breast cancer cells, TMEM97 deficiency attenuated Wnt/beta-catenin signaling and suppressed tumorigenic properties, suggesting that targeting TMEM97 could be a promising therapeutic strategy for breast cancer.
CELL DEATH & DISEASE
(2021)
Review
Cell Biology
Qian Ren, Jiongcheng Chen, Youhua Liu
Summary: LRP5 and LRP6 are crucial in mediating Wnt signaling, with similar functions but also distinct characteristics, as they interact with different protein partners, each possessing its own unique functions. Understanding the precise roles of LRP5 and LRP6 may help in identifying and refining therapeutic targets for various human diseases.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Chemistry, Multidisciplinary
Jian Zhang, Mengmeng Qin, Dan Yang, Lan Yuan, Xiajuan Zou, Wenbing Dai, Hua Zhang, Xueqing Wang, Bing He, Qiang Zhang
Summary: A large number of proteins are involved in the delivery and transport of nanomedicines, playing a key role in mediating drug delivery and ensuring drug safety. The EV/ER/Golgi/SV pathway was found to dominate the transcytosis of nanoparticles across the epithelial barrier. Furthermore, the association of the Wnt/beta-catenin signaling pathway with nanoparticle transportation was discovered, with the regulatory effect varying based on particle size.
Review
Cell Biology
Wonyoung Jeong, Eek-hoon Jho
Summary: Wnt signaling pathway, particularly Wnt/beta-catenin signaling, is crucial in development and tissue homeostasis, with dysregulation of components like LRP6 implicated in diseases such as cancer, neurodegeneration, metabolic syndrome, and skeletal disease. The molecular mechanisms by which LRP6 senses Wnt and transduces downstream signaling cascades are still being deciphered, highlighting the complexity and importance of this pathway in various physiological and pathological processes.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Oncology
Hanqing Wang, Sidi Zhao, Yang Liu, Fengyuan Sun, Xiaoming Huang, Tong Wu
Summary: This study demonstrates that downregulation of SOST promotes the malignant progression of uveal melanoma by activating the Wnt/beta-catenin signaling pathway. Mechanistically, SOST may exert this function by interacting with LRP5/LRP6 membrane receptors.
FRONTIERS IN ONCOLOGY
(2022)
Article
Dentistry, Oral Surgery & Medicine
M. Yu, Z. Fan, S. W. Wong, K. Sun, L. Zhang, H. Liu, H. Feng, Y. Liu, D. Han
Summary: This study identified novel LRP6 mutations in patients with tooth agenesis, with some patients carrying harmful mutations in the Lrp6 gene. The research also revealed dynamic changes in the expression pattern of Lrp6 during tooth development, providing insights into the functional significance of Lrp6 in biological processes.
JOURNAL OF DENTAL RESEARCH
(2021)
Article
Oncology
Xia Liao, Yaoyao Zhang, Binghui Xu, Arshad Ali, Xin Liu, Qingan Jia
Summary: Hepatocellular carcinoma (HCC) is a serious issue in China, with limited efficacy of oxaliplatin in treatment. The potential protective effect of inositol hexaphosphate (IP6) in preventing HCC progression has been studied in combination with oxaliplatin, showing independent anticancer and synergistic anti-proliferative effects. The study suggests that IP6 treatment makes HCC cells sensitive to oxaliplatin by disrupting the CCN2-LRP6-beta-catenin-ABCG1 signaling pathway.
Review
Pharmacology & Pharmacy
Avradip Chatterjee, Sayan Paul, Bharti Bisht, Shelley Bhattacharya, Sudhakar Sivasubramaniam, Manash K. Paul
Summary: This review explores the role of WNT/b-catenin signaling in various physiological processes and its association with cancer, examining potential targets and inhibitors for therapy. Clinical trials on inhibitors and potential new strategies, including AI-assisted tools, are also discussed for translating WNT/b-catenin inhibitors for cancer therapy.
DRUG DISCOVERY TODAY
(2022)
Article
Biochemistry & Molecular Biology
Gareth Hall, Eilish Cullen, Kovilen Sawmynaden, Joanne Arnold, Simon Fox, Richard Cowan, Frederick W. Muskett, David Matthews, Andrew Merritt, Catherine Kettleborough, William Cruikshank, Debra Taylor, Richard Bayliss, Mark D. Carr
JOURNAL OF BIOLOGICAL CHEMISTRY
(2016)
Article
Biochemistry & Molecular Biology
Eva Lorinczi, Matthew Helliwell, Alina Finch, Phillip J. Stansfeld, Noel W. Davies, Martyn Mahaut-Smith, Frederick W. Muskett, John S. Mitcheson
JOURNAL OF BIOLOGICAL CHEMISTRY
(2016)
Article
Endocrinology & Metabolism
Maura Agostini, Erik Schoenmakers, Junaid Beig, Louise Fairall, Istvan Szatmari, Odelia Rajanayagam, Frederick W. Muskett, Claire Adams, A. David Marais, Stephen O'Rahilly, Robert K. Semple, Laszlo Nagy, Amit R. Majithia, John W. R. Schwabe, Dirk J. Blom, Rinki Murphy, Krishna Chatterjee, David B. Savage
Article
Biochemistry & Molecular Biology
Daniel Stoeppler, Alex Macpherson, Susanne Smith-Penzel, Nicolas Basse, Fabien Lecomte, Herve A. Deboves, Richard D. Taylor, Tim Norman, John Porter, Lorna C. Waters, Marta Westwood, Ben Cossins, Katharine Cain, James White, Robert Griffin, Christine Prosser, Sebastian Kelm, Amy H. Sullivan, David Fox, Mark D. Carr, Alistair Henry, Richard Taylor, Beat H. Meier, Hartmut Oschkinat, Alastair D. Lawson
Article
Biophysics
Alice M. Barkell, Gill Holdsworth, Lorna C. Waters, Vaclav Veverka, Patrick M. Slocombe, Frederick W. Muskett, Alistair J. Henry, Martyn K. Robinson, Mark D. Carr
BIOMOLECULAR NMR ASSIGNMENTS
(2015)
Article
Multidisciplinary Sciences
Rebekka Schairer, Gareth Hall, Ming Zhang, Richard Cowan, Roberta Baravalle, Frederick W. Muskett, Peter J. Coombs, Chido Mpamhanga, Lisa R. Hale, Barbara Saxty, Justyna Iwaszkiewicz, Chantal Decaillet, Mai Perroud, Mark D. Carr, Margot Thome
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2020)
Article
Biochemistry & Molecular Biology
Lorna C. Waters, Vaclav Veverka, Sarah L. Strong, Frederick W. Muskett, Neesha Dedi, Alastair D. G. Lawson, Christine E. Prosser, Richard J. Taylor, Alistair J. Henry, Mark D. Carr
Summary: IL-17A and IL-17F, as key proinflammatory cytokines, play crucial roles in human inflammatory diseases, forming dimers with striking conformational dynamic differences in binding to IL-17RA, which may contribute to their varying affinities.
Article
Biophysics
Kayleigh Walker, Lorna C. Waters, Geoff Kelly, Frederick W. Muskett, Mark D. Carr
Summary: The interaction between PD-1 and PD-L1 plays a regulatory role in T-cell activation and self-tolerance. Over-expression of PD-L1 allows tumor cells to evade immune system detection. While therapeutic antibodies targeting PD-L1 or PD-1 have been approved for cancer treatment, developing small-molecule inhibitors of PD-L1 remains challenging. This study reports the specific sequence assignments of PD-L1, which will be useful for the discovery of small-molecule therapeutics and the characterization of its functional interactions with other protein partners.
BIOMOLECULAR NMR ASSIGNMENTS
(2022)
Article
Chemistry, Multidisciplinary
Rachel L. Norman, Rajinder Singh, Frederick W. Muskett, Emma L. Parrott, Alessandro Rufini, James Langridge, Franscois Runau, Ashley Dennison, Jacqui A. Shaw, Elena Piletska, Francesco Canfarotta, Leong L. Ng, Sergey Piletsky, Donald J. L. Jones
Summary: This study utilized nano molecularly imprinted polymers (nanoMIPs) to capture the critical oncogene KRAS, allowing for the determination of mutations and discovery of epitopes using LC-MS technology. The approach demonstrated the potential for precise genotyping of cancer cell lines and patients through the use of nanoMIPs, indicating a promising translation from research to clinical utility.
Article
Biophysics
Li-Ying Lin, S. E. Evans, L. Fairall, John W. R. Schwabe, Simon D. Wagner, Frederick W. Muskett
BIOMOLECULAR NMR ASSIGNMENTS
(2018)