[R35] Genetic and Molecular Dissection of Wnt Pathway Activation
Ente: National Institute of General Medical Sciences
Scadenza: 2030-07-31
Importo max: 628.000 EUR
Paese: US
Descrizione
PROJECT SUMMARY
Tissue specification, growth, maintenance, and regeneration rely on spatiotemporal cues provided by the
evolutionarily conserved Wnt morphogen pathway. Many developmental disorders and cancers, including
nearly all colorectal cancers, arise when the normal regulation of Wnt signal transduction is lost; yet key
mechanisms that mediate essential steps in this pathway remain poorly understood. An improved mechanistic
understanding of Wnt pathway activation is therefore crucial, as no drugs that target Wnt-driven disease have
yet been approved by the FDA. The long-term goals of the PI’s research program are to uncover the
foundational mechanisms that control Wnt signaling during animal development and to use this knowledge to
identify vulnerabilities in the pathway that are susceptible to therapeutic targeting in Wnt-driven diseases. To
support these goals, the PI and her laboratory group have developed innovative, cost-effective approaches in
the fruit fly Drosophila that provide three major strengths to surmount existing obstacles in the field: cutting-
edge genetic tools, limited functional redundancy, and robust in vivo assays for Wnt signaling gradients.
Research by the PI’s group identified two novel roles for the tumor suppressor Adenomatous polyposis coli
(APC) in Wnt signaling, two novel transcription cofactors required for nearly all consequences of APC loss, the
dual mechanisms by which the therapeutic target Tankyrase activates Wnt signaling, and a Wnt receptor
regulatory mechanism required to tune signaling strength throughout the morphogen gradient. This project will
address major questions centered on the three multi-protein complexes that control Wnt signaling: 1) How is
the activity of the membrane-associated signalosome complex controlled by regulation of the Wnt receptor
LRP6/Arrow?; 2) How are the components of the nuclear beta-catenin-TCF transcription complex activated by
phosphorylation and ubiquitylation?; and 3) How is the activity of the two key kinases in the cytosolic beta-
catenin destruction complex, GSK3 and CK1, modulated under basal conditions and following Wnt stimulation?
To address these questions, the research capitalizes on state-of-the-art genetic and proteomic screens that
have identified six new enzymatic regulators that control the activity of these essential complexes. The function
of each will be defined using a combination of genetic, cell biological, and biochemical assays. The impact of
this research is enhanced by long-term collaborations that incorporate complementary experimental
approaches, including biochemical reconstitution, quantitative phosphoproteomics, and vertebrate models that
test evolutionarily conserved functions. The successful completion of this work will provide a strong
mechanistic understanding of this fundamental signaling pathway and highlight new therapeutic strategies to
target Wnt-driven diseases.
Istituzione: DARTMOUTH COLLEGE
PI: Yasmath Ahmed
Progetto: 5R35GM136233-07
Settori: National Institute of General Medical Sciences
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