# Bi-directional regulation of chemokine receptor signaling

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2022 · $306,114

## Abstract

PROJECT SUMMARY
Cervical cancer remains one of the leading causes of cancer-related deaths world-wide. A large body of
evidence indicates that a sub-family of G protein-coupled receptors (GPCRs), known as chemokine receptors,
are linked to progression of several cancers, including cervical cancer. Dysregulated signaling of certain
chemokine receptors correlates with poor prognosis in cervical cancer, yet the mechanisms remain poorly
understood. The overall objective of this proposal is to determine the mechanisms governing chemokine
receptor regulation in the context of cervical cancer growth and metastasis. This is significant because these
studies will define new targets for clinical potential. Specifically, we will focus on a novel paradigm that governs
chemokine receptor bi-directional regulation by A kinase anchoring proteins (AKAPs). AKAPs are scaffolding
proteins that bind and nucleate multiple proteins, usually belonging to a common signaling pathway, to spatially
and temporally control signaling to drive physiological responses. We performed a siRNA screen of AKAPs
expressed in HeLa cells, a cervical cancer cell line, and provide evidence that AKAPs are involved in cross-
regulation of chemokine receptor trafficking. Further, using biochemical and biophysical approaches we
provide evidence that chemokine receptors reside in a compartment with AKAPs and protein kinas C (PKC),
but that other GPCRs are excluded. It is possible that chemokine receptors might co-reside in a sub-
compartment at the plasma membrane that enables their cross-regulation without input from other GPCRs,
likely to exclusively fine tune their signaling. Based on published and new preliminary data we hypothesize that
chemokine receptors are part of a multimeric protein complex compartmentalized by AKAPs that governs their
bi-directional regulation. To test this hypothesis we will pursue three specific aims. Aim 1: To determine the
role of PKC in bi-directional chemokine receptor regulation; Aim 2: To determine the role of AKAPs in
chemokine receptor bi-directional trafficking and signaling; and Aim 3: To determine the role of bi-directional
chemokine receptor regulation in cervical cancer in vitro and in vivo. At the conclusion of the proposed studies
we expect to determine the mechanism of bi-directional regulation of chemokine receptor signaling.
Importantly, we expect to establish that novel aspects of chemokine receptor regulation and signaling could be
targeted to treat cervical cancer.

## Key facts

- **NIH application ID:** 10471999
- **Project number:** 5R01GM143808-02
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Adriano Marchese
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $306,114
- **Award type:** 5
- **Project period:** 2021-09-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10471999

## Citation

> US National Institutes of Health, RePORTER application 10471999, Bi-directional regulation of chemokine receptor signaling (5R01GM143808-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10471999. Licensed CC0.

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