A5040139302- Wnt/β-catenin signaling in development and cancer
- Cancer-related gene regulation
- Invertebrate Immune Response Mechanisms
- Ubiquitin and proteasome pathways
- Digestive system and related health
- Hippo pathway signaling and YAP/TAZ
- RNA Research and Splicing
- Developmental Biology and Gene Regulation
- Kruppel-like factors research
- Epigenetics and DNA Methylation
- Polyamine Metabolism and Applications
- Genetics and Neurodevelopmental Disorders
- Neurobiology and Insect Physiology Research
- Protein Degradation and Inhibitors
- Histone Deacetylase Inhibitors Research
- Hedgehog Signaling Pathway Studies
- Retinal Development and Disorders
- Toxin Mechanisms and Immunotoxins
- Genetic factors in colorectal cancer
- Cellular transport and secretion
- Galectins and Cancer Biology
- Helicobacter pylori-related gastroenterology studies
- Ocular Disorders and Treatments
- Congenital gastrointestinal and neural anomalies
- Nuclear Receptors and Signaling
Dartmouth College
2016-2025
Princeton University
1998-2002
Abstract Background New pharmacologic targets are urgently needed to treat or prevent lung cancer, the most common cause of cancer death for men and women. This study identified one such target. is canonical Wnt signaling pathway, which deregulated in cancers, including those lacking adenomatous polyposis coli β-catenin mutations. Two poly-ADP-ribose polymerase (PARP) enzymes regulate activity: tankyrase (TNKS) 1 TNKS2. These poly-ADP-ribosylate (PARsylate) destabilize axin, a key component...
Intestinal stem cell (ISC) self-renewal and proliferation are directed by Wnt/β-catenin signaling in mammals, whereas aberrant Wnt pathway activation ISCs triggers the development of human colorectal carcinoma. Herein, we have utilized Drosophila midgut, a powerful model for ISC regulation, to elucidate mechanisms which Wingless (Wg)/Wnt regulates intestinal homeostasis development. We provide evidence that Wg pathway, peaks at each major compartment boundaries adult intestine, has essential...
Abstract Wnt/β-catenin signalling directs fundamental processes during metazoan development and can be aberrantly activated in cancer. Wnt stimulation induces the recruitment of scaffold protein Axin from an inhibitory destruction complex to a stimulatory signalosome. Here we analyse early effects on find that ADP-ribose polymerase Tankyrase (Tnks)—known target for proteolysis—regulates Axin’s rapid transition following stimulation. We demonstrate pool ADP-ribosylated Axin, which is degraded...
The comprehensive understanding of cellular signaling pathways remains a challenge due to multiple layers regulation that may become evident only when the pathway is probed at different levels or critical nodes are eliminated. To discover regulatory mechanisms in canonical WNT signaling, we conducted systematic forward genetic analysis through reporter-based screens haploid human cells. Comparison for negative, attenuating and positive regulators mediators R-spondin-dependent suppressors...
Inactivation of the Adenomatous Polyposis Coli (APC) tumor suppressor triggers development most colorectal carcinomas. APC is required for targeted degradation beta-catenin, central transcriptional activator in Wnt/Wingless (Wg) signal transduction pathway; however, precise biochemical functions remain uncertain. The two Drosophila homologs (Apc1 and Apc2) appear to have predominantly different tissue distributions, subcellular localizations mutually exclusive phenotypes upon inactivation....
ABSTRACT Wnt/β-catenin signaling controls intestinal stem cell (ISC) proliferation, and is aberrantly activated in colorectal cancer. Inhibitors of the ADP-ribose polymerase Tankyrase (Tnks) have become lead therapeutic candidates for Wnt-driven cancers, following recent discovery that Tnks targets Axin, a negative regulator Wnt signaling, proteolysis. Initial reports indicated important pathway activation cultured human lines. However, requirement physiological settings has been less clear,...
Abstract Immunomodulatory drugs (IMiDs) are important for the treatment of multiple myeloma and myelodysplastic syndrome. Binding IMiDs to Cereblon (CRBN), substrate receptor CRL4 CRBN E3 ubiquitin ligase, induces cancer cell death by targeting key neo-substrates degradation. Despite this clinical significance, physiological regulation remains largely unknown. Herein we demonstrate that Wnt, extracellular ligand an essential signal transduction pathway, promotes CRBN-dependent degradation a...
Abstract The relative abundance of Wnt receptors plays a crucial role in controlling signaling tissue homeostasis and human disease. While the ubiquitin ligases that ubiquitylate are well-characterized, deubiquitylase reverses these reactions remains unclear. Herein, we identify USP46, UAF1, WDR20 (USP46 complex) as positive regulators cultured cells. We find USP46 complex is similarly required for Xenopus zebrafish embryos. demonstrate promotes association between cell surface coreceptor,...
The Wnt–β-catenin signal transduction pathway is essential for embryonic development and adult tissue homeostasis. Wnt signaling converts TCF from a transcriptional repressor to an activator in process facilitated by the E3 ligase XIAP. XIAP-mediated monoubiquitylation of corepressor Groucho (also known as TLE) decreases its affinity TCF, thereby allowing coactivator β-catenin displace it on TCF. Through genome-scale screen cultured Drosophila melanogaster cells, we identified deubiquitylase...
The evolutionarily conserved Wnt/Wingless signal transduction pathway directs cell proliferation, fate, and death during development in metazoans is inappropriately activated several types of cancer. majority colorectal carcinomas contain truncating mutations the adenomatous polyposis coli (APC) tumor suppressor, a negative regulator signaling. Here, we demonstrate that Drosophila Apc homologs also have an activating role both physiological ectopic Wingless amino terminus important for its...
Signal transduction activated by Wingless/Wnt ligands directs cell proliferation and fate specification in metazoans, its overactivation underlies the development of vast majority colorectal cancers. In conventional model, secretion movement Wingless to cells distant from source synthesis are essential for long-range signaling tissue patterning. However, this model was upended recently an unanticipated finding: replacement wild-type Drosophila with a membrane-tethered form produced viable...
Wnt ligands are considered classical morphogens, for which the strength of cellular response is proportional to concentration ligand. Herein, we show an emergent property bistability arising from feedback among destruction complex proteins that target key transcriptional co-activator β-catenin degradation. Using biochemical reconstitution, identified positive between scaffold protein Axin and kinase glycogen synthase 3 (GSK3). Theoretical modeling this GSK3 suggested activity exhibits...
Abstract Wnt/β-catenin signal transduction directs metazoan development and is deregulated in numerous human congenital disorders cancers. In the absence of Wnt stimulation, a multiprotein “destruction complex,” assembled by scaffold protein Axin, targets key transcriptional activator β-catenin for proteolysis. Axin maintained at very low levels that limit destruction complex activity, property currently being exploited novel therapeutics Wnt-driven Here, we use an vivo approach Drosophila...
The aberrant activation of Wnt signal transduction initiates the development 90% colorectal cancers, majority which arise from inactivation tumor suppressor Adenomatous polyposis coli (APC). In classical model for signaling, primary role APC is to act, together with concentration-limiting scaffold protein Axin, in a "destruction complex" that directs phosphorylation and consequent proteasomal degradation transcriptional activator β-catenin, thereby preventing signaling Wnt-off state....
Wnt/β-catenin signal transduction directs intestinal stem cell (ISC) proliferation during homeostasis. Hyperactivation of Wnt signaling initiates colorectal cancer, which most frequently results from truncation the tumor suppressor Adenomatous polyposis coli (APC). The β-catenin-TCF transcription complex activates both physiological expression target genes in normal epithelium and their aberrantly increased tumors. Whether mechanistic differences machinery drive these distinct levels gene...
Deregulation of the Wnt signal transduction pathway underlies numerous congenital disorders and cancers. Axin, a concentration-limiting scaffold protein, facilitates assembly "destruction complex" that prevents signaling in unstimulated state plasma membrane-associated "signalosome" activates following stimulation. In classical model, Axin is cytoplasmic under basal conditions, but relocates to cell membrane after exposure; however, due very low levels endogenous this model based largely on...