# A Novel Role for MAGI1 in regulating non-canonical LATS signaling and atherosclerotic plaque formation

> **NIH NIH R01** · METHODIST HOSPITAL RESEARCH INSTITUTE · 2021 · $380,587

## Abstract

Project Summary
Pro-atherogenic stimuli such as inflammatory cytokines and disturbed flow (d-flow) significantly contribute to
endothelial cell (EC) inflammation, and subsequent atherosclerotic plaque formation. Membrane-associated
guanylate kinase-1 (MAGI1) is a scaffold protein that contains six PSD95/DiscLarge/ZO-1 (PDZ) domains, a
guanylate kinase domain, and two WW domains flanked by the first and second PDZ domains. MAGI1 associates
with the tight and adherens junction, but its cytosolic and nuclear localization has also been reported. Recently,
a genome-wide association study has revealed a strong association of mutations in Magi1 gene locus with
inflammatory bowel disease and psoriatic arthritis. The significant contribution of EC inflammation in regulating
the phenotype and severity of these diseases, which are also clinically associated with accelerated
atherosclerosis (AS) and increased risk of cardiovascular diseases, has been well established. In the preliminary
data, we have found the critical role of MAGI1 post-translational modifications (PTMs) in regulating EC
inflammation and apoptosis. MAGI1 S741 phosphorylarion results in the activation of Rap1 and large tumor
suppressor 1 (LATS1) (but not Yes-associated protein [YAP] phosphorylation, which is a canonical pathway
regulated by LATS1). MAGI1 de-SUMOylation leads to the co-translocation of MAGI1 and p90RSK to the
nucleus, where they up-regulate inflammatory gene expression. In the proposed study, we hypothesize that
dynamic modulation of MAGI1 PTMs (phosphorylation and de-SUMOylation) leads to cytosolic Rap1 and non-
canonical LATSs signaling activation, and p90RSK nuclear translocation. MAGI1 in both cytosolic and nuclear
compartments plays critical roles in regulating EC inflammation and apoptosis and subsequent atherogenesis.
Aim 1 will identify the mechanism by which MAGI1 S741 phosphorylation promotes EC inflammation and
apoptosis. Aim 2 will determine the role of MAGI1 de-SUMOylation in nuclear translocation and promoting EC
inflammation. In aim 3, we will determine the role of MAGI1 and LATS1/2 in accelerating AS. The concept of the
MAGI1 PTMs including phosphorylation- and de-SUMOylation-induced EC inflammation is novel and highlights
the importance of determining how this PDZ domain-containing molecule and p90RSK coordinately regulate EC
inflammation and apoptosis. The long–term goals of this project are to identify the role of MAGI1 phosphorylation
and (de)SUMOylation in regulating MAGI1 subcellular localization and MAGI1-dependent signaling and to
elucidate the molecular mechanisms by which MAGI1 induces EC inflammation and apoptosis and promotes
atherogenesis. This will provide deeper understanding of the basic signaling responsible for the poor outcome
of AS-related cardiovascular diseases.

## Key facts

- **NIH application ID:** 10112287
- **Project number:** 5R01HL134740-05
- **Recipient organization:** METHODIST HOSPITAL RESEARCH INSTITUTE
- **Principal Investigator:** Nhat-Tu Le
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $380,587
- **Award type:** 5
- **Project period:** 2017-01-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10112287

## Citation

> US National Institutes of Health, RePORTER application 10112287, A Novel Role for MAGI1 in regulating non-canonical LATS signaling and atherosclerotic plaque formation (5R01HL134740-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10112287. Licensed CC0.

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