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Nox1-based NADPH oxidase regulates the Par protein complex activity to control cell polarization
Alejandra Valdivia1, Charity Duran1, Mingyoung Lee1
1Division of Cardiology, Department of Medicine, School of Medicine, Emory University, Atlanta, GA, United States.
Frontiers in Cell and Developmental Biology
|August 28, 2023
Summary
Nox1 deficiency impairs cell polarity and lamellipodium formation by disrupting the Par3/aPKC complex and inactivating PP2A phosphatase. Hydrogen peroxide (H2O2) addition rescues these defects, highlighting Nox1
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Cell migration is vital for biological and pathological processes, requiring precise front-rear polarity and lamellipodium formation.
- The partitioning-defective (Par) protein complex (Par3, Par6, aPKC) and small GTPases (Rac, Cdc42, RhoA) are key regulators of cell polarity and migration.
- Nox1-based NADPH oxidase is implicated in growth factor-induced cell migration.
Purpose of the Study:
- To investigate the role of Nox1 in establishing cell polarity and regulating the Par complex during cell migration.
- To elucidate the molecular mechanisms by which Nox1 deficiency affects cell polarity and lamellipodium formation.
- To assess the physiological relevance of the Nox1-PP2A-aPKC signaling axis in a mouse model of neointimal hyperplasia.
Main Methods:
- Analysis of cell polarity, MTOC positioning, and lamellipodium formation in Nox1-deficient cells.
- Investigation of Par3, Tiam, Rac1, aPKC, and PP2A phosphatase activity in response to Nox1 deficiency and H2O2 treatment.
- Validation in Nox1-deficient primary mouse aortic smooth muscle cells (MASMCs) and a femoral artery wire injury model.
Main Results:
- Nox1-deficient cells exhibit defective front-rear polarity, MTOC polarization, and single lamellipodium formation, instead forming multiple protrusions.
- Nox1 deficiency leads to PP2A phosphatase inactivation and subsequent aPKC activation, causing hyperactivation of Par3, Tiam, and Rac1.
- Exogenous H2O2 rescues the migration defects in Nox1-deficient cells; Nox1-/- mice show reduced neointimal hyperplasia, linked to PP2A and aPKC activity.
Conclusions:
- Nox1 is essential for establishing cell polarity and proper lamellipodium formation, likely through regulating PP2A phosphatase and aPKC activity.
- The Nox1-PP2A-aPKC signaling pathway plays a critical role in controlling cell migration and has implications in vascular remodeling.
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