# Mechanisms of Signaling Protein Retention in the Primary Cilium

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $313,000

## Abstract

PROJECT SUMMARY
 The primary cilium is a solitary membrane extrusion from the apical surface of noncycling resting
cells in mammals. It functions as a sensory organelle that is responsible for the resting cells to sense
environmental conditions and communicate with adjacent cells. This organelle is composed of a
microtubule-based axoneme encased in the plasma membrane, resulting in formation of a ciliary
compartment that is separated from the cytoplasm by a transition zone at its base. Protein trafficking
within the ciliary compartment is mediated by intraflagellar transport that transverses the compartment bi-
directionally on the microtubules. Accumulating evidence suggests that the ability of the primary cilium to
function as a sensory organelle depends on selective accumulation of various signaling molecules. Many
components of cilium-dependent pathways are found to be transported into and out of the primary cilium
in response to environmental cues. However, the mechanisms underlying the regulated trafficking remain
unknown.
 The proposed application is to define a previously unknown mechanism in intraflagellar protein
trafficking that as suggested by our preliminary data, regulates ciliary accumulation of soluble protein
kinases in response to flow stress and chemical stimulation. This novel mechanism is mediated by
folliculin (FLCN), a tumor suppressor, of which defects cause the Birt-Hogg-Dube (BHD) syndrome, a
genetic disorder that is manifested clinically by benign tumors and cystic growth in multiple organs. In
ciliated resting cells inactivation of FLCN produces profound effects on several major cilium-dependent
pathways, including the Sonic Hedgehog (Shh) pathway, which becomes fully active and unresponsive to
ligand stimulation. Preliminary data suggest that FLCN couples Shh ligand stimulation to ciliary
accumulation and activation of Smoothened (Smo), a key but poorly understood step in Shh signaling.
The application is proposed to define the underlying molecular basis and its functional significance in
general ciliary signaling. Three lines of investigation will be carried out in the context of ligand and flow
stress regulated Shh signaling. including: 1) determining how FLCN-mediated ciliary protein accumulation
controls Smo activation in response to Shh ligand stimulation; 2) determining the role of Rab23 small
GTPase in the ciliary function of FLCN; 3) determining how flow stress controls Shh signaling through
FLCN. Successful completion of the proposed studies will offer a new paradigm to explain how ciliary
signaling is regulated by environmental cues and elucidate the mechanism underlying the Shh ligand-
induced activation of Smo.

## Key facts

- **NIH application ID:** 9935100
- **Project number:** 5R01GM132127-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** YU JIANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $313,000
- **Award type:** 5
- **Project period:** 2019-05-24 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9935100

## Citation

> US National Institutes of Health, RePORTER application 9935100, Mechanisms of Signaling Protein Retention in the Primary Cilium (5R01GM132127-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9935100. Licensed CC0.

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