# Control of MAPK Signaling by Cell Polarity Proteins

> **NIH NIH R01** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2021 · $344,931

## Abstract

Signal transduction pathways function in interconnected networks comprising
common or shared proteins. How specific signals are directed through a common
protein module to induce a highly specific response is not clear. Some diseases like
cancer can arise because a signal that is meant to follow one path is misdirected into
another. One MAPK pathway in yeast regulates a microbial differentiation response
called filamentous growth. In fungal pathogens, filamentous growth is required for
virulence. The MAPK pathway is composed of G proteins and protein kinases that
function in multiple pathways. A major regulator of the pathway is the Rho GTPase,
Cdc42, which is widely considered a master regulator of cell polarity and signaling.
In this proposal is reported the discovery that Cdc42 is degraded by a mechanism
that involves ubiquitin modification of the protein. This discovery is important
because it provides a new way to regulate signaling pathways that require Cdc42 for
function. Thus, one objective of the proposal is to determine the functional
consequences of Cdc42 turnover on MAP kinase signaling (Aim 1). In addition to
Cdc42, several protein kinases are shared among MAPK pathways. In Aim 2, a
newly identified scaffold of the Ral GDS type will be examined that binds to kinases
to direct them to the MAPK pathway. The filamentous growth pathway is regulated
by a sensor protein of the mucin family. Mucins are large glycoproteins that regulate
signaling pathways through mechanisms that remain uclear. In Aim 3 of the
proposal, how the mucin connects to and regulates Cdc42 will be determined. One
candidate is the cell's main polairty scaffold, which has recently been found to also
regulate the MAPK pathway. Experiments are proposed to determine how the mucin
directs the polarity scaffold to the Cdc42 module. Collectively, this proposal will
define new mechanisms of G protein regulation, as well as how commom proteins
are directed to specific pathways. Given that the proteins in this pathway are highly
conserved from yeast to humans, insights gained from this proposal will likely extend
to signaling pathways in general, including those that are relevant to human health.

## Key facts

- **NIH application ID:** 10211615
- **Project number:** 2R01GM098629-10A1
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** Paul James Cullen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $344,931
- **Award type:** 2
- **Project period:** 2011-09-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10211615

## Citation

> US National Institutes of Health, RePORTER application 10211615, Control of MAPK Signaling by Cell Polarity Proteins (2R01GM098629-10A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10211615. Licensed CC0.

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