# Posttranslational regulation of Regulator of G protein Signaling 2 (RGS2)

> **NIH NIH R01** · PURDUE UNIVERSITY · 2022 · $300,637

## Abstract

Project Summary
 Regulator of G protein Signaling (RGS) proteins play a key modulatory role in G Protein-coupled receptor
(GPCR) signaling. Through both G protein-dependent and -independent mechanisms, RGS proteins play
important roles in disease, and this has driven numerous efforts to pharmacologically target their function. These
efforts are, however, hindered by the fact that RGS proteins are considered difficult drug targets, and identifying
mechanisms that control RGS protein activity, expression and/or subcellular localization has therefore become
an important area of investigation. Our long-term goal is to determine how levels and activity of RGS proteins is
regulated, with a view of identifying druggable “soft-spots” within the regulatory network. Our rationale for the
current proposal is that identification of specific mechanisms regulating RGS2 will uncover therapeutic points of
intervention to increase RGS protein levels and activity. Low RGS2 protein levels or activity are associated with
a wide range of pathologies, including hypertension, heart failure and asthma, and our central hypothesis is that
pharmacologically enhancing RGS2 protein levels would have broad clinical implications. Our objective in this
proposal is to decipher posttranslational mechanisms regulating expression, activity and subcellular localization
of RGS2. We will focus on two crucial, but understudied, mechanisms regulating RGS2 protein levels and activity;
proteasomal degradation and phosphorylation. We identified a Cullin-RING E3 ligase (CRL) targeting RGS2 for
proteasomal degradation, and recently identified the degron in RGS2 that is recognized by F-box only protein
44 (FBXO44), the substrate-recognizing component of the CRL. In Aim 1 we will use biochemical and structural
approaches to determine how FBXO44 interacts with RGS2. We will also determine whether FBXO44-RGS2
binding is determined by the associated CRL. FBXO44 degrades RGS2 only in the context of a CUL4B/DDB1,
but not a CUL1/Skp1 complex in cells suggesting that FBXO44 RGS2 specificity may depend on the nature of
the CRL. In Aim 2 we will determine the role of phosphorylation for RGS2 function. Phosphorylation plays a
central role in signal transduction cascades, however there is a lack of comprehensive information on the global
role of phosphorylation for RGS2 protein function. Our previous studies identified potential importance for PKC
and Src kinase in regulating RGS2. We will determine which residues are phosphorylated, as well as the
consequence for RGS2 protein stability, using a wide range of techniques, including PhosTag gel
electrophoresis, in vitro kinase activity assays, as well as LC-MS. In Aim 3 we will determine the functional
consequences of altered posttranslational RGS2 regulation. We will determine effects on G protein-dependent
and -independent RGS2 functions in both transfected cells, physiologically relevant cell lines and ex vivo models.
The expected outcome of these studi...

## Key facts

- **NIH application ID:** 10446200
- **Project number:** 1R01GM143493-01A1
- **Recipient organization:** PURDUE UNIVERSITY
- **Principal Investigator:** Benita Jenny Sjogren
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $300,637
- **Award type:** 1
- **Project period:** 2022-09-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10446200

## Citation

> US National Institutes of Health, RePORTER application 10446200, Posttranslational regulation of Regulator of G protein Signaling 2 (RGS2) (1R01GM143493-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10446200. Licensed CC0.

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