Reciprocal Association between the Apical Junctional Complex and AMPK: A Promising Therapeutic Target for Epithelial/Endothelial Barrier Function?

Abstract

Epithelial/endothelial cells adhere to each other via cell–cell junctions including tight junctions (TJs) and adherens junctions (AJs). TJs and AJs are spatiotemporally and functionally integrated, and are thus often collectively defined as apical junctional complexes (AJCs), regulating a number of spatiotemporal events including paracellular barrier, selective permeability, apicobasal cell polarity, mechano-sensing, intracellular signaling cascades, and epithelial morphogenesis. Over the past 15 years, it has been acknowledged that adenosine monophosphate (AMP)-activated protein kinase (AMPK), a well-known central regulator of energy metabolism, has a reciprocal association with AJCs. Here, we review the current knowledge of this association and show the following evidences: (1) as an upstream regulator, AJs activate the liver kinase B1 (LKB1)–AMPK axis particularly in response to applied junctional tension, and (2) TJ function and apicobasal cell polarization are downstream targets of AMPK and are promoted by AMPK activation. Although molecular mechanisms underlying these phenomena have not yet been completely elucidated, identifications of novel AMPK effectors in AJCs and AMPK-driven epithelial transcription factors have enhanced our knowledge. More intensive studies along this line would eventually lead to the development of AMPK-based therapies, enabling us to manipulate epithelial/endothelial barrier function.

Dehydrocostus Lactone Attenuates Methicillin-Resistant Staphylococcus aureus-Induced Inflammation and Acute Lung Injury via Modulating Macrophage Polarization

“…Moreover, DHL was found to exert these effects via regulating macrophage polarization through the p38 MAPK/NF-κB and AMPK/Nrf2 signaling pathways. The p38 MAPK/NF-κB and AMPK/Nrf2 signaling pathways are also related to endothelial and epithelial activation [ 57 , 58 , 59 , 60 ], and may contribute to enhancing neutrophil infiltration and pulmonary damage [ 61 , 62 ]. Therefore, further studies should focus on whether DHL provides protective effects on endothelial and epithelial activation.…”

α1AMP-Activated Protein Kinase Protects against Lipopolysaccharide-Induced Endothelial Barrier Disruption via Junctional Reinforcement and Activation of the p38 MAPK/HSP27 Pathway

“…Moreover, α1AMPK activation leads to the phosphorylation of HSP27 via a non-canonical p38 MAPK dependent mechanism, which results in the reinforcement of the submembrane actin network during LPS challenge, contributing to the consolidation of IEJs in the plasma membrane and intercellular tethering (Figure 8). Therefore, α1AMPK activation might have therapeutic potential to alleviate conditions in which microvascular barrier formation is dramatically compromised, such as sepsis [88].…”

A microtubule‐LUZP1 association around tight junction promotes epithelial cell apical constriction

“…Here, we provide conceptual advances by revealing a crucial ppMLC‐triggered system at CRs around TJs—hereafter referred to as TJ‐associated CRs (Fig EV1A)—for vertebrate apical constriction involving LUZP1, myosin phosphatase, and MTs. The apical MTs, which are different from classical apicobasal MTs, are reportedly associated with TJs in a side‐by‐side manner, in a variety of epithelial cells (Fig EV1B) (Kunimoto et al , 2012; Yano et al , 2013; Matter & Balda, 2014; Herawati et al , 2016; Toya & Takeichi, 2016; Yano et al , 2017; Takeda et al , 2018; Yano et al , 2018; Citi, 2019; Tsukita et al , 2019a). To further elucidate the role of MTs in cell–cell junctions, we conducted unbiased screening for MT‐associated proteins in an AJC‐enriched fraction and identified LUZP1.…”