# Regulation of Hippo and PCP signaling by the protocadherins Fat and Dachsous

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $306,000

## Abstract

Project Summary
The giant Drosophila protocadherins Fat and Dachsous (Ds) form a heterophilic, bidirectional signaling pair
that regulates proliferation via the growth-inhibiting Hippo pathway, and planar cell polarity (PCP) both through
and independently of the “core” PCP pathway. These functions are shared by their mammalian homologs, and
human mutations in Fat and Ds cause the neurological and multisystem defects of Hennekam and Van
Maldergem syndromes. Despite its importance, only a little is known about how binding between Fat and Ds
change cell behavior, and thus how it regulates development and pathology.
Fat, Ds and the effectors of the Hippo and PCP pathways are concentrated in the subapical domain of
epithelial cells, and the intracellular domain (ICD) of Fat has strong effects on the subapical levels of two
critical proteins. The first is the scaffolding myosin Dachs, which binds and inhibits Warts (Lats1/2), the final
effector kinase in the Hippo pathway, and which regulates Sple in the core PCP pathway. The second is the
FERM scaffolding protein Expanded, which stimulates Warts activity. However, the physical and biochemical
links between the Fat ICD, Dachs and Expanded have never been established.
Using a combination of protein-binding screens, biochemistry and genetics, we have for the first time filled that
physical gap, and in a way that provides a strong working model for the biochemistry of Fat signal transduction.
The Fat ICD binds two proteins, the DHHC palmitoyltransferase Approximated (App), and the newly
discovered SH3 adaptor protein Dlish. Our data indicates that Fat inhibits the palmitoylation of Dlish through
App and thereby its affinity for and accumulation near the subapical cell membrane. In fat mutants,
membrane-associated Dlish increases, directly binding Dachs and recruiting it to the subapical cell cortex,
where Dachs inhibits Warts. Dlish also directly binds Expanded and reduces its levels and Warts-stimulating
activity, likely through regulated ubiquitination. We propose experiments designed to rigorously test and
extend our understanding of this important and unusual signaling pathway, moving from in vitro to in vivo
assays and analyses, investigating parallel and alternative pathways, and identifying new pathway
components.

## Key facts

- **NIH application ID:** 9923677
- **Project number:** 5R01GM124377-04
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** SETH S BLAIR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $306,000
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9923677

## Citation

> US National Institutes of Health, RePORTER application 9923677, Regulation of Hippo and PCP signaling by the protocadherins Fat and Dachsous (5R01GM124377-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9923677. Licensed CC0.

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