A5049509028- Wnt/β-catenin signaling in development and cancer
- Cancer-related gene regulation
- Peptidase Inhibition and Analysis
- Ubiquitin and proteasome pathways
- Biochemical and Structural Characterization
- Chemical Synthesis and Analysis
- DNA and Nucleic Acid Chemistry
- RNA and protein synthesis mechanisms
- Click Chemistry and Applications
- Hippo pathway signaling and YAP/TAZ
- Advanced biosensing and bioanalysis techniques
- Monoclonal and Polyclonal Antibodies Research
- Cellular transport and secretion
- Epigenetics and DNA Methylation
- RNA modifications and cancer
- Glycosylation and Glycoproteins Research
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Neuropeptides and Animal Physiology
- Endoplasmic Reticulum Stress and Disease
- Cell death mechanisms and regulation
- Toxin Mechanisms and Immunotoxins
- Hedgehog Signaling Pathway Studies
- RNA Interference and Gene Delivery
- Axon Guidance and Neuronal Signaling
Case Western Reserve University
2024
Biolog (United States)
2024
Genentech
2007-2014
Boston Children's Hospital
2013
Harvard University
2004-2013
National University of Singapore
2012
Agency for Science, Technology and Research
2012
Duke-NUS Medical School
2012
PDL BioPharma (United States)
2010
Scripps Research Institute
2009
Abstract Porcupine (PORCN) is a membrane bound O-acyltransferase that required for Wnt palmitoylation, secretion, and biologic activity. All evaluable human Wnts require PORCN their activity, suggesting inhibition of could be an effective treatment cancers dependent on excess In this study, we evaluated the inhibitor Wnt-C59 (C59), to determine its activity toxicity in cultured cells mice. C59 inhibits vitro at nanomolar concentrations, as assessed by interaction with carrier protein...
Snakebite envenoming is a serious and neglected tropical disease that kills ~100,000 people annually. High-quality, genome-enabled comprehensive characterization of toxin genes will facilitate development effective humanized recombinant antivenom. We report de novo near-chromosomal genome assembly Naja naja, the Indian cobra, highly venomous, medically important snake. Our has scaffold N50 223.35 Mb, with 19 scaffolds containing 95% genome. Of 23,248 predicted protein-coding genes, 12,346...
Wnt/beta-catenin signaling is initiated at the cell surface by association of secreted Wnt with its receptors Frizzled (Fz) and low density lipoprotein receptor-related protein 5/6 (LRP5/6). The study these molecular interactions has been a significant technical challenge because proteins have inaccessible in sufficient purity quantity. In this report we describe insect expression purification soluble mouse Fz8 cysteine-rich domain human LRP6 extracellular show that they inhibit cellular...
β-catenin-dependent Wnt signaling is initiated as binds to both the receptor FZD and coreceptor LRP5/6, which then assembles a multimeric complex at cytoplasmic membrane face recruit inactivate kinase GSK3. The large number sequence diversity of isoforms suggest possibility domain-specific ligand-coreceptor interactions, distinct binding sites on LRP6 for Wnt3a Wnt9b have recently been identified in vitro. Whether mechanistically different interactions between Wnts coreceptors might mediate...
Axon degeneration initiated by trophic factor withdrawal shares many features with programmed cell death, but prior studies discounted a role for caspases in this process, particularly Caspase-3. Recently, Caspase-6 was implicated based on pharmacological and knockdown evidence, we report here that genetic deletion of indeed provides partial protection from degeneration. However, find at biochemical level is activated effectively only Caspase-3 not other “upstream” caspases, prompting us to...
Receptor-interacting protein kinase 4 (RIPK4) is required for epidermal differentiation and mutated in Bartsocas-Papas syndrome. RIPK4 binds to C, but its signaling mechanisms are largely unknown. Ectopic RIPK4, not catalytically inactive or mutants, induced accumulation of cytosolic β-catenin a transcriptional program similar that caused by Wnt3a. In Xenopus embryos, Ripk4 synergized with coexpressed Xwnt8, whereas morpholinos catalytic antagonized Wnt signaling. interacted constitutively...
Frizzled (FZD) receptors mediate Wnt signaling in diverse processes ranging from bone growth to stem cell activity. Moreover, high FZD receptor expression at the surface contributes overactive subsets of pancreatic, ovarian, gastric, and colorectal tumors. Despite progress biochemical understanding Wnt-FZD interactions, molecular basis for recognition cis-unsaturated fatty acyl groups by cysteine-rich domain (CRD) remains elusive. Here, we determined a crystal structure human FZD7 CRD...
Abstract Cellular senescence and the senescence-associated secretory phenotype (SASP) are implicated in aging age-related disease, SASP-related inflammation is thought to contribute tissue dysfunction diseased animals. However, whether how SASP factors influence regenerative capacity of tissues remains unclear. Here, using intestinal organoids as a model regeneration, we show that released by senescent fibroblasts deregulate stem cell activity differentiation ultimately impair crypt...
Wnt morphogens are critical for embryonic development and tissue regeneration. Canonical Wnts form ternary receptor complexes composed of tissue-specific Frizzled (Fzd) receptors together with the shared LRP5/6 coreceptors to initiate β-catenin signaling. The cryo-EM structure a initiation complex an affinity-matured XWnt8–Frizzled8–LRP6 elucidates basis coreceptor discrimination by canonical means their N termini linker domains that engage LRP6 E1E2 domain funnels. Chimeric bearing modular...
Fatty acylation or lipid modification of proteins controls their cellular activation and diverse roles in physiology. It mediates protein-protein protein-membrane interactions plays an important role regulating signaling pathways. Currently, there is need for visualizing modifications cells. Herein we report novel chemical probes based on omega-alkynyl fatty acids biochemical detection imaging lipid-modified proteins. Our study shows that varying chain length are metabolically incorporated...
Polyubiquitination is an essential posttranslational modification that plays critical roles in cellular signaling. PolyUb (polyubiquitin) chains are formed by linking the carboxyl-terminus of one Ub (ubiquitin) subunit to either a lysine residue or amino-terminus adjacent Ub. Linkage through results linear polyubiquitination has recently been demonstrated be key step nuclear factor κB activation; however, tools study have lacking. We therefore engineered linear-linkage-specific antibody...
A total synthesis of the complex, bent aromatic ring-containing marine alkaloid haouamine is achieved through a route in which every step (with exception final deprotection) performed on gram-scale. This accomplished development method for dehydrogenation cyclohexenones that allows point-to-planar chirality transfer. strategy makes it possible to program desired atropisomeric outcome from simple chiral cyclohexenone. By synthesizing atrop-haouamine A, this work has firmly established natural...
Hedgehog protein undergoes post-translational palmitoylation, which is critical for its signaling activity during embryonic development and in adult tissues. Due to a lack of suitable imaging methods, the trafficking route palmitoylated has remained unclear secretory cells. Here, we report novel method subcellular distribution forms cellular proteins with high resolution. The utilizes clickable chemical reporters label entire proteome, followed by proximity ligation on antibodies...
Cyclotides belong to the family of cyclic cystine‐knot peptides and have shown promise as scaffolds for protein engineering pharmacological modulation cellular activity. are characterized by a cystine‐knotted topology head‐to‐tail polypeptide backbone. While they primarily produced in plants, cyclotides also been obtained chemical synthesis. However, there is still need methods generate high yields near homogeneity. Here, we report biomimetic approach which utilizes an engineered version...
Peptides present an alternative modality to immunoglobulin domains or small molecules for developing therapeutics either agonize antagonize cellular pathways associated with diseases. However, peptides often suffer from poor chemical and physical stability, limiting their therapeutic potential. Disulfide-constrained (DCP) are naturally occurring possess numerous desirable properties, such as high that qualify them drug-like scaffolds peptide therapeutics. DCPs contain loop regions protruding...