# Deciphering the functional role of actin-spectrin-based membrane skeleton in subcellular compartmentalization of signaling proteins and cell signal transduction

> **NIH NIH R35** · PENNSYLVANIA STATE UNIVERSITY, THE · 2022 · $249,751

## Abstract

Project Summary/Abstract:
Receptor tyrosine kinases (RTKs), G-protein-coupled receptors (GPCRs), and cell adhesion
molecules (CAMs) are three major families of cell surface proteins in all eukaryotic cells, and
together represent the primary first responders for cells to respond an extracellular stimulus and
initiates a variety of signaling pathways to subsequently regulate cell proliferation and
differentiation, promote cell survival, and modulate cellular metabolism and cell-to-cell
communication. Mutations affecting these signaling pathways result in many human syndromes
and diseases, such as various types of neurodegenerative disorders and cancer. The clinical
importance of these signaling proteins has motivated the development of targeted therapies
designed to block the activation of the membrane receptors and the downstream signal
transduction. Increasing evidence has suggested that there is significant signaling crosstalk
between these three membrane protein families at the plasma membrane level and these proteins
can form highly organized membrane micro- or nano-clusters with unique biochemical and
biophysical properties, dictating the signaling outcome. However, the molecular mechanisms by
which how such crosstalk and compartmentalization of membrane-associated signaling proteins
are initiated to modulate the sensitivity and specificity of the downstream signaling remain largely
elusive. Our recent discovery of a newly identified actin-spectrin-based membrane-associated
periodic skeleton (MPS) structure being a signaling platform for RTK transactivation by GPCRs
and CAMs in neurons provides molecular insights into how the cooperative action among these
cell surface proteins can be coordinated to give rise to the downstream signaling. The objective
of this proposal is to combine super-resolution imaging, cell and molecular biology tools, and
mass spectrometry analyses, to investigate the detailed molecular mechanisms responsible for
the MPS-mediated cell signaling, by identifying the key molecular interactions responsible for the
MPS-dependent initiation of the signaling protein clustering (i.e., complex formation) and
examining the roles of liquid-liquid phase separation, receptor endocytosis, and contact sites
between the plasma membrane and intracellular membrane-bound intracellular organelles in the
MPS-mediated signaling. Our proposed research will not only broaden our fundamental
understanding of cell signal transduction controlled by the membrane skeleton and the phase
separation behaviors of signaling proteins, but also help suggest new drug targets for human
diseases including neurodegenerative diseases and cancer.

## Key facts

- **NIH application ID:** 10580148
- **Project number:** 3R35GM142973-01S1
- **Recipient organization:** PENNSYLVANIA STATE UNIVERSITY, THE
- **Principal Investigator:** Ruobo Zhou
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $249,751
- **Award type:** 3
- **Project period:** 2021-09-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10580148

## Citation

> US National Institutes of Health, RePORTER application 10580148, Deciphering the functional role of actin-spectrin-based membrane skeleton in subcellular compartmentalization of signaling proteins and cell signal transduction (3R35GM142973-01S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10580148. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*