# Protein dynamics underlying cilium-dependent Hedgehog signaling

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $65,625

## 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:** 11099312
- **Project number:** 3R01GM145651-03S1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Radhika Subramanian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $65,625
- **Award type:** 3
- **Project period:** 2022-09-20 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11099312

## Citation

> US National Institutes of Health, RePORTER application 11099312, Protein dynamics underlying cilium-dependent Hedgehog signaling (3R01GM145651-03S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11099312. Licensed CC0.

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