Feedback-Driven Mechanisms Between Phosphorylated Caveolin-1 and Contractile Actin Assemblies Instruct Persistent Cell Migration

Xuemeng Shi; Zeyu Wen; Yajun Wang; Yan-Jun Liu; Kun Shi; Yaming Jiu

doi:10.3389/fcell.2021.665919

Feedback-Driven Mechanisms Between Phosphorylated Caveolin-1 and Contractile Actin Assemblies Instruct Persistent Cell Migration

Front Cell Dev Biol. 2021 Apr 12:9:665919. doi: 10.3389/fcell.2021.665919. eCollection 2021.

Authors

Xuemeng Shi^{1

2}, Zeyu Wen^{3

4}, Yajun Wang⁵, Yan-Jun Liu⁵, Kun Shi^{1

2}, Yaming Jiu^{1

2

3

4}

Affiliations

¹ The Joint Program in Infection and Immunity, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
² The Joint Program in Infection and Immunity, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
³ Key Laboratory of Molecular Virology and Immunology, The Center for Microbes, Development and Health, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
⁴ University of Chinese Academy of Sciences, Beijing, China.
⁵ Shanghai Institute of Cardiovascular Diseases, and Institutes of Biomedical Sciences, Zhongshan Hospital, Fudan University, Shanghai, China.

Abstract

The actin cytoskeleton and membrane-associated caveolae contribute to active processes, such as cell morphogenesis and motility. How these two systems interact and control directional cell migration is an outstanding question but remains understudied. Here we identified a negative feedback between contractile actin assemblies and phosphorylated caveolin-1 (CAV-1) in migrating cells. Cytoplasmic CAV-1 vesicles display actin-associated motilities by sliding along actin filaments or/and coupling to do retrograde flow with actomyosin bundles. Inhibition of contractile stress fibers, but not Arp2/3-dependent branched actin filaments, diminished the phosphorylation of CAV-1 on site Tyr14, and resulted in substantially increased size and decreased motility of cytoplasmic CAV-1 vesicles. Reciprocally, both the CAV-1 phospho-deficient mutation on site Tyr14 and CAV-1 knockout resulted in dramatic AMPK phosphorylation, further causing reduced active level of RhoA-myosin II and increased active level of Rac1-PAK1-Cofilin, consequently led to disordered contractile stress fibers and prominent lamellipodia. As a result, cells displayed depolarized morphology and compromised directional migration. Collectively, we propose a model in which feedback-driven regulation between actin and CAV-1 instructs persistent cell migration.

Keywords: Arp2/3 complex-dependent lamellipodia; actin filaments; actomyosin bundles; caveolin-1; directional cell migration.