# Role of beta-arrestins in chemokine receptor signaling

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2021 · $398,687

## Abstract

PROJECT SUMMARY
The heterotrimeric G protein-coupled receptor (GPCR) C-X-C motif receptor 4 (CXCR4) and its cognate ligand
CXCL12 play important roles in health and disease. A large body of evidence indicates that CXCR4 signaling
is linked to cancer progression. CXCR4 expression and signaling in cancer correlates with poor prognosis2-5,
mainly because cancer cells expressing CXCR4 colonize distant anatomical sites where CXCL12 is located,
resulting in metastatic disease, the cause of most cancer related deaths. CXCR4 signaling regulates several
aspects of cell physiology linked to cancer progression. This includes directed cell migration and cell survival,
which occur via several discrete signaling pathways. Yet the mechanisms remain poorly understood. The focus
of this proposal is on the signal transduction mechanisms that regulate CXCR4-mediated chemotaxis towards
CXCL12. We recently reported that CXCR4-mediated chemotaxis occurs via a novel mechanism involving a
complex formed between endocytic adaptor proteins b-arrestin1 (barr1) and STAM1 (barr1:STAM1). The
barr1:STAM1 complex does not act on Akt or ERK-1/2 signaling pathways, but instead is necessary for
activating focal adhesion kinase (FAK), which is also necessary for CXCL12 driven chemotaxis. FAK is
typically linked to integrin signaling and focal adhesion dynamics, but these aspects of FAK function are not
regulated by the barr1:STAM1 complex. Despite our contribution how barr1:STAM1 activates FAK downstream
of CXCR4 to promote chemotaxis remains poorly understood. The overall objective of this proposal is to fill in
knowledge gaps. Based on our published and preliminary studies we hypothesize that G protein-dependent
barr1:STAM1 signaling spatially and temporally controls FAK activity required for CXCR4-dependent
chemotaxis. To test this hypothesis we will pursue the following specific aims: Aim 1. To elucidate the role of
CXCR4 site-specific phosphorylation on FAK activation; Aim 2. To identify the structural and biophysical
properties of the barr1 interaction with STAM1; Aim 3. To elucidate the functional role of the barr1:STAM1
complex in chemotaxis. Because of the mechanistic focus of our proposal we will use cell culture models and
other in vitro approaches spanning techniques in cell and molecular biology, genetics, biochemistry and
biophysics plus advanced live cell imaging strategies and mass spectrometry approaches. At the conclusion of
this project we will have learned novel signal transduction mechanisms by which barr1:STAM1 collaborate to
activate FAK to promote chemotaxis. This is significant because it will reveal novel aspects of CXCR4
signaling that could be targeted therapeutically.

## Key facts

- **NIH application ID:** 10142489
- **Project number:** 5R01GM106727-08
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Adriano Marchese
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $398,687
- **Award type:** 5
- **Project period:** 2014-02-11 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10142489

## Citation

> US National Institutes of Health, RePORTER application 10142489, Role of beta-arrestins in chemokine receptor signaling (5R01GM106727-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10142489. Licensed CC0.

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