# Protein dynamics underlying cilium-dependent Hedgehog signaling

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $336,000

## Abstract

ABSTRACT
The Hedgehog (Hh) signaling pathway is a major intercellular signaling pathway important for embryonic
development and adult tissue homeostasis. Errors in Hh signaling are linked to several newborn birth defects
such as skeletal malformations and craniofacial defects, and associated with multiple tumors including basal
cell carcinoma and medulloblastoma. An important but poorly understood aspect of vertebrate Hh signaling is
the strict requirement of a microtubule-based organelle known as the primary cilium. While we now have a
wealth of data on the “parts-list” of proteins involved in the Hh signaling, the molecular mechanisms underlying
cilia-mediated signal transduction remains poorly understood. Our overall goal is to fill this major knowledge
gap and provide a biochemical framework for the Hh signaling pathway by reconstituting key reaction of this
pathway from its components. For this research, we will build on our experience in integrating single-molecule
imaging methods with biochemical assays and cell biological readouts to connect the biochemical properties of
the protein components to their cellular function. In this proposal, we focus a key step of the Hh signal
transduction pathway which is the establishment of signaling complexes at the base and the tip of the cilia, as
is needed for the proper activation or repression of the transcription factor Gli, the major effector of the Hh
pathway. Here, we will: (1) define these protein-protein interactions through a series of reconstitution studies
and determine how they restrict the Gli binding to the nuclear import machinery and (2) analyze the dynamics
of key pathway proteins in the cilium using high-resolution real-time imaging. Together, these studies will
define how Gli is regulated through dynamic transit between protein complexes at defined cytoplasmic
locations. We expect that our findings will not only advance our understanding of the basic biology of this
important signal transduction pathway but also shed light on how mutations in pathway components contribute
to developmental disorders and human cancers.

## Key facts

- **NIH application ID:** 10418376
- **Project number:** 1R01GM145651-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Radhika Subramanian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $336,000
- **Award type:** 1
- **Project period:** 2022-09-20 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10418376

## Citation

> US National Institutes of Health, RePORTER application 10418376, Protein dynamics underlying cilium-dependent Hedgehog signaling (1R01GM145651-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10418376. Licensed CC0.

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