# G protein-coupled receptor signaling in development and disease: Hedgehog and beyond

> **NIH NIH R35** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $415,800

## Abstract

Our lab studies how transmembrane proteins signal from the cell's external environment to its interior during
animal development and adulthood, how dysregulation of transmembrane signaling leads to disease, and how
to correct pathological transmembrane signaling via novel mechanism-inspired therapeutic strategies. We focus
on the Hedgehog (Hh) pathway, a fundamental signaling cascade that specifies the development of nearly every
vertebrate organ and ensures homeostasis during adulthood. Hh also serves as a leading model for signal
transduction within the primary cilium, a tiny antenna-shaped protrusion found on nearly every cell in the body
that is critical for G protein-coupled receptor (GPCR) cascades in many physiological systems. While the
importance of Hh signaling in health and disease is clear, the biochemical mechanisms underlying the central
steps in this cascade are surprisingly mysterious. Our MIRA program focuses on three central problems in Hh
and GPCR signaling: 1) How are Hh signals received and deciphered at the cell surface? 2) How are Hh signals
transmitted intracellularly? 3) Why must many GPCRs localize to the cilium to perform their biological functions?
Our seminal contributions from the work of our first MIRA include: 1) Defining the biochemical and structural
mechanism of activation for SMOOTHENED (SMO), an atypical GPCR and the key transducer of Hh signals at
the ciliary membrane. We found that SMO is activated by cholesterol, which binds to a site deep within the SMO
membrane-spanning domain; and 2) Demonstrating that SMO signals intracellularly via a mechanism
unprecedented in GPCR biology: SMO directly binds the protein kinase A (PKA) catalytic subunit and physically
blocks its enzymatic activity. These discoveries have generated new principles regarding how cholesterol can
serve as a GPCR’s key activating “switch”, and how GPCRs can directly regulate the activity of kinases.
The next phase of our MIRA builds on this foundation, tackling a number of the outstanding questions in the
field. We will learn how SMO is regulated by the Hh receptor and putative sterol transporter PTCH1, test our
mechanistic model for SMO activity using in vivo Hh signal transduction systems, and learn how SMO-PKA
signaling is regulated by lipids proteins, post-translational modifications, and pathway deactivation mechanisms.
Finally, we will embark on a new research direction, using the concepts and tools from our Hh studies to test
roles for cholesterol and phosphorylation codes in the operation of ciliary GPCRs. Together, these investigations
will advance our understanding of the signal transduction mechanisms underlying Hh and other ciliary GPCR
cascades, with broad implications for development, physiology, and disease. These studies will also enable the
generation of diagnostic and therapeutic tools for a range of devastating disorders, including congenital defects,
malignancies, and dysfunction of the nervous, cardiovascular, and muscul...

## Key facts

- **NIH application ID:** 10842952
- **Project number:** 2R35GM133672-06
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Benjamin Myers
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $415,800
- **Award type:** 2
- **Project period:** 2019-08-07 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10842952

## Citation

> US National Institutes of Health, RePORTER application 10842952, G protein-coupled receptor signaling in development and disease: Hedgehog and beyond (2R35GM133672-06). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10842952. Licensed CC0.

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