# Membrane Targeting and Retargeting of Polarity Proteins

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $19,919

## Abstract

Administrative Supplement – Abstract
 Establishing and maintaining apical-basal polarity is essential for epithelial tissue
integrity and function under both normal and stressed conditions such as hypoxia/ischemia. A
group of so-called polarity proteins play essential and conserved functions in regulating cell
polarity in both invertebrates and vertebrates. One key feature of all polarity proteins is that
association with plasma membrane (PM) or cell cortex is critical for their in vivo functions. With
few exceptions, most polarity proteins are assumed to be localized to PM/cell cortex through
protein-protein interactions. Regulatable molecular mechanisms underlying the potential direct
interaction between PM and majority of polarity proteins have long been elusive. Polybasic
domains that are rich in positively charged Arg and Lyn residues have a well-established role in
PM-specific targeting, based on its electrostatic interactions with negatively charged
polyphosphoinositides PI4P and PIP2 that are uniquely enriched on the PM inner surface.
However, for decades functional studies on polybasic domain in PM targeting have been limited
to a small number of proteins and no polybasic domains had been characterized in any of the
polarity proteins.
 We recently identified Lgl as the first polarity protein that contains an evolutionarily
conserved and phosphorylatable polybasic domain whose electrostatic binding to PI4P and PIP2
on the PM directly mediate the PM localization of Lgl. In this proposal we have identified that
many additional polarity proteins, as well as hundreds to thousands of proteins in Drosophila
and human genomes, also contain potential polybasic domains. We will use both Drosophila
and cultured mammalian cells to investigate the hypothesis that electrostatic binding between
polybasic domain and plasma membrane serves a key regulatable molecular mechanism for
controlling the subcellular localizations of multiple polybasic polarity proteins. We will confirm
the electrostatic binding of PM by multiple polybasic polarity proteins. More importantly, we will
investigate the molecular mechanisms such as phosphorylation, allosteric regulation and
coincident protein interactions that may control the direct binding between PM and polybasic
proteins to achieve their polarized subcellular localization and activations. Finally, our research
highlighted for the first time that hypoxia and depletion of ATP acutely and reversibly inhibit
polybasic domain proteins PM targeting through depleting PI4P and PIP2 on the PM. Our
research revealed a previously unappreciated but biologically significant challenge for cells to
retarget polybasic polarity proteins to original PM domains after hypoxia/ischemia. We will focus
on identifying mechanisms that actively direct the retargeting of polybasic polarity proteins to
their original PM domains.
 Our research will establish a new paradigm to understand how regulatable binding
between polybasic domains and PM...

## Key facts

- **NIH application ID:** 10133938
- **Project number:** 3R01GM121534-04S1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Yang Hong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $19,919
- **Award type:** 3
- **Project period:** 2017-04-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133938

## Citation

> US National Institutes of Health, RePORTER application 10133938, Membrane Targeting and Retargeting of Polarity Proteins (3R01GM121534-04S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10133938. Licensed CC0.

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