# Molecular mechanisms of Wnt and mechanical signaling through β-catenin

> **NIH NIH R35** · STANFORD UNIVERSITY · 2021 · $188,289

## Abstract

The development and homeostasis of solid tissues depends upon biochemical and mechanical signals that
control cell fate and the resulting organization of cells in the tissue. The conserved protein β-catenin is a key
effector of signals from both the Wnt family of secreted growth factors that specify cell fate during
embryogenesis and tissue renewal in the adult, and mechanical force transmitted through cell-cell junctions
in multicellular tissues. We hypothesize that mechanical force transmitted through β-catenin links Wnt
signaling and cell-cell adhesion, and our overall goal is to understand the molecular mechanisms underlying
these dual roles of β-catenin. Our strategy is to use biochemical, structural and biophysical methods to
address critical knowledge gaps in these areas.
In the absence of Wnts, the β-catenin is bound in a “destruction complex” that includes the proteins Axin
and Adenomatous Polyposis Coli (APC), and kinases that phosphorylate β-catenin; phosphorylation leads
to ubiquitylation and destruction of β-catenin by the proteasome. Wnt binding to the receptors Frizzled (Fzd)
and LRP5/6 enables Fzd to recruit the cytoplasmic protein Dishevelled (Dvl), which in turn binds to Axin and
thereby recruits the destruction complex to the activated receptor complex. This leads to phosphorylation of
the LRP5/6 intracellular domain, which inhibits β-catenin destruction; the stabilized β-catenin enters the
nucleus and activates target genes. We will address critical mechanistic aspects of this pathway that are not
understood: 1) how secreted ligands “activate” the Fzd-Dvl interaction needed for β-catenin stabilization
through interaction with the extracellular cysteine-rich domain of Fzd and LRP5/6; 2) how activated Dvl
recruits Axin to turn off β-catenin destruction; 3) how the β-catenin destruction complex forms and interacts
with the ubiquitylation/proteosomal machinery; 4) the essential role of APC in β-catenin destruction.
Force transmission through cell-cell adherens junctions (AJ) requires a complex of E-cadherin, β-catenin,
and α-catenin, which binds to actin filaments and forms a minimal force-sensing unit. Tension on cadherins
can release β-catenin and cause its translocation to the nucleus independent of, but synergized by, Wnt
signaling. Understanding such tension-triggered release of β-catenin requires understanding how force is
transmitted through the AJ complex. α-Catenin additionally has a central role in organizing epithelial tissues
based on its interactions with vinculin, Epithelial Protein Lost in Neoplasm (EPLIN), the tight junction (TJ)
protein Zonula Occludens (ZO)-1, and afadin, all of which bind actin and recruit other scaffolding and
signaling proteins. We will study: 1) The force-dependent conformational landscape and force
responsivness of α-catenin alone and bound to its partners, including how β-catenin modifies α-catenin
force responsiveness; 2) How αE-catenin conformation and force transmission properties are af...

## Key facts

- **NIH application ID:** 10299581
- **Project number:** 3R35GM131747-02S1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** William I Weis
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $188,289
- **Award type:** 3
- **Project period:** 2019-06-07 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10299581

## Citation

> US National Institutes of Health, RePORTER application 10299581, Molecular mechanisms of Wnt and mechanical signaling through β-catenin (3R35GM131747-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10299581. Licensed CC0.

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