Digging for Therapeutic Gold: Prospecting for Targets in the Wnt Signaling Pathway
Posted August 11, 2006
The large family of Wnts—highly conserved, critically important secreted signaling molecules found in both vertebrates and invertebrates—function as both morphogens and growth factors in the embryo and the adult. The Wnt receptors and signaling pathways are thought to constitute the most complex relationship between extracellular ligands and receptors identified to date.
Dysfunctional Wnt/β-catenin signaling—which creates continuous transcription of the many target genes supporting cell proliferation—has now been documented in a wide range of cancers, including colorectal cancer, melanoma, gastric cancer, and tumors derived from hepatic, breast, and prostate tissue. Mutations in the β-catenin pathway are also linked to bone density syndromes and to neurodegenerative diseases, and may be involved in the retinal disease familial exudative vitreoretinopathy and in Alzheimer's disease.
An October 25, 2005, meeting at the Academy brought together four investigators whose laboratories are helping to define the therapeutic potential of the Wnt signaling pathway.
Connections Map Overviews
Science magazine's Signal Transduction Knowledge Environment provides a Connections Map on the Wnt/β-catenin pathway with detailed annotation of most pathway components as well as two animated movies. The Abstract is available here, and the menu on the left provides links for text, for the pathway, for a table of associated human diseases, and for the signaling animations. (Subscription required.)
Growth Factor and Receptor Tyrosine Kinases
This Teaching Resource by Stuart Aaronson from Science's Signal Transduction Knowledge Environment provides lecture notes and slides for a graduate-level class on ligand regulation of signaling by receptor tyrosine kinases and receptors involved in the Wnt canonical pathway. It is part of a series of lectures that constitute the Cell Signaling Systems course. A description of the lecture, along with a set of slides used to present this information, is provided.
Laboratory of Randall Moon
The Moon lab website is the major repository of available cDNAs in the field. Click on "Reagents" for more information.
The Wnt Homepage
Gathering everything about Wnts under one roof, and doing so in a highly user-friendly format, this exceedingly useful Wnt resource is compiled, maintained, and updated (every 6 months) by Roel Nusse—one of the pioneers in Wnt research and discovery—at Stanford University Medical Center. A history page for timeline additions provides a bird's-eye view of the most recent updates and discoveries.
New Insights into Wnt Receptor Activation in Human Cancer Cells
Bafico, A., G. Liu, L. Goldin, et al. 2004. An autocrine mechanism for constitutive Wnt pathway activation in human cancer cells. Cancer Cell 6: 497-506.
Bafico, A., G. Liu, A. Yaniv, et al. 2001. Novel mechanism of Wnt signaling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow. Nat. Cell Biol. 3: 683-686.
Liu, G., A. Bafico & S. A. Aaronson. 2005. The mechanism of endogenous receptor activation functionally distinguishes prototype canonical and noncanonical Wnts. Mol. Cell Biol. 25: 3475-3482. Full Text
Liu, G., A. Bafico, V. K. Harris & S. A. Aaronson. 2003. A novel mechanism for Wnt activation of canonical signaling through the LRP6 receptor. Mol. Cell Biol. 23: 5825-5835. Full Text
β-catenin Dysfunction in Intestinal Tumorigenesis
Hinoi, T., G. Gesina, A. Akyol, et al. 2005. CDX2-regulated expression of iron transport protein hephaestin in intestinal and colonic epithelium. Gastroenterology 128: 946-961.
Hinoi, T., M. Tani, P. C. Lucas, et al. 2001. Loss of CDX2 expression and microsatellite instability are prominent features of large cell minimally differentiated carcinomas of the colon. Am. J. Pathol. 159: 2239-2248. Full Text
Kolligs, F. T., B. Kolligs, K. M. Hajra, et al. 2000. γ-catenin is regulated by the APC tumor suppressor and its oncogenic activity is distinct from that of β-catenin. Genes Dev. 14: 1319-1331.
Qualtrough, D., T. Hinoi, E. R. Fearon & C. Paraskeva. 2002. Expression of CDX2 in normal and neoplastic human colon tissue and during differentiation of an in vitro model system. Gut. 51: 184-190. Full Text
Wu, R., Y. Zhai, E. R. Fearon & K. R. Cho. 2001. Diverse mechanisms of β-catenin deregulation in ovarian endometrioid adenocarcinomas. Cancer Res. 61: 8247-8255. Full Text
Zhai, Y., R. Wu, D. R. Schwartz, et al. 2002. Role of β-catenin/T-cell factor-regulated genes in ovarian endometrioid adenocarcinomas. Am. J. Pathol. 160: 1229-1238. Full Text
β-catenin as Therapy and Therapeutic Target
Angers, S., C. J. Thorpe, T. L. Biechele, et al. 2006. The KLHL12-Cullin-3 ubiquitin ligase negatively regulates the Wnt-beta-catenin pathway by targeting Dishevelled for degradation. Nat. Cell Biol. 8: 348-357.
Chien, A. J., R. T. Moon. 2007. WNTS and WNT receptors as therapeutic tools and targets in human disease processes. Front. Biosci. 12: 448-457.
DasGupta, R., A. Kaykas, R. T. Moon & N. Perrimon. 2005. Functional genomic analysis of the Wnt-wingless signaling pathway. Science 308: 826-833.
Fathke, C., L. Wilson, K. Shah, et al. 2006. Wnt signaling induces epithelial differentiation during cutaneous wound healing. BMC Cell Biol. 7: 4. Full Text (PDF, 1.5 MB)
Kaykas, A., J. Yang-Snyder, M. Heroux et al. 2004. Mutant Frizzled 4 associated with vitreoretinopathy traps wild-type Frizzled in the endoplasmic reticulum by oligomerization. Nat. Cell Biol. 6: 52-58.
Robitaille, J., M. L. MacDonald, A. Kaykas, et al. 2002. Mutant Frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy. Nat. Genet. 32: 326-330.
Stoick-Cooper, C. L., G. Weidinger, K. J. Riehle, et al. 2007. Distinct Wnt signaling pathways have opposing roles in appendage regeneration. Development 134: 479-489.
Wnt Signaling in Cancers Lacking Pathway Mutations
Polakis, P. 1999. The oncogenic activation of β-catenin. Curr. Opin. Genet. Dev. 9: 15-21.
Shulewitz, M., I. Soloviev, T. Wu, et al. 2006. Repressor roles for TCF-4 and Sfrp1 in Wnt signaling in breast cancer. Oncogene Mar 13. [Epub ahead of print]
Stuart A. Aaronson, MD
Stuart Aaronson is the Jack and Jane B. Aron Professor and chairman of the department of oncological sciences at the Mount Sinai School of Medicine. In his early studies, Aaronson established that mammalian sarcoma viruses are capable of transformation but are defective in replication and went on to clone many of their oncogenes. His laboratory now focuses on cancer gene discovery: his current research includes investigations into the mechanisms by which tumor suppressor genes induce permanent growth arrest and senescence. He also studies the signaling pathways involved in this process.
Aaronson received his MD degree from the University of San Francisco. He joined the National Institutes of Health in 1967 and became chief of the laboratory of cellular and molecular biology at the National Cancer Institute in 1977. Aaronson is the recipient of numerous awards including the Distinguished Service Medal from the U.S. Public Health Service, the Rhoads Memorial Award from the American Association of Cancer Research, and the Paul Erhlich Prize from Germany. He is the author of over 530 publications, an inventor on more than 50 patents, and a member of numerous editorial boards and scientific advisory committees.
Eric R. Fearon, MD, PhD
Eric Fearon is professor of internal medicine, human genetics, and pathology at the University of Michigan. He is also the associate director for basic science at the University of Michigan Cancer Center. The research in Fearon's laboratory seeks to address the means by which specific oncogene and tumor suppressor gene defects contribute to the pathogenesis of colon and other cancers. Present areas of emphasis include studies of the APC/β-catenin/Tcf, CDX2, and E-cadherin pathways, as well as gene expression profiling of colorectal cancers.
Fearon received his medical and doctoral degrees from Johns Hopkins University. He completed his postdoctoral training at the hematology division of the department of medicine and the oncology center. Fearon has been awarded the David Israel Macht Prize for Basic Science Research by Johns Hopkins and the Wilson S. Stone Award by the University of Texas M.D. Anderson Cancer Center. He also served as McDonnell fellow in molecular medicine in cancer research.
Randall T. Moon, PhD
Randall Moon is professor of pharmacology and director of the center for developmental biology at the University of Washington School of Medicine. He studies the biochemistry of the Wnt signal transduction pathways and the role of these pathways in vertebrate embryonic development. He is interested in understanding the role of Wnt signaling in diseases and in using this understanding to develop potential therapies.
Moon received his PhD degree from the department of zoology at the University of Washington. His postdoctoral research was conducted at the California Institute of Technology. After returning to the University of Washington, he was a Syntex scholar in cardiovascular research. He is a recipient of a research career development award from the National Institutes of Health and the T.L.L. Temple Foundation Discovery Award of the Alzheimers Association.
Paul Polakis, PhD
Paul Polakis is a senior scientist at Genetech, Inc. He heads the tumor antigen project in an effort to identify tumor cell markers that will serve as targets for therapeutic antibodies. He is currently working on identifying antigens that are expressed on the surface of human cancer cells. The overall goal of this project is to raise antibodies to these antigens that will ultimately serve as therapeutics in the treatment of cancer. He also works on the Wnt signaling pathway, which is often defected in human colorectal cancer.
Polakis received his PhD in biochemistry from Michigan State University and went on to become assistant professor of chemistry at Oberlin College. He then worked as a postdoctoral research associate at the Duke University Medical Center. He joined Genetech as a postdoctoral research associate in 1987 and, after working at Cetus Corporation and Onyx Pharmaceuticals, returned as senior scientist in 1999.
Sheila Sperber Haas
Sheila Sperber Haas is a freelance science and health care writer living in New York City who writes about issues ranging from molecular biology and immunology to complementary and alternative medicine. Her varied projects include Dermatology Focus, bringing the forefront of molecular investigative dermatology to a clinical readership.