Abstract
Tight junctions (TJ) play an essential role in the epithelial barrier. By definition, TJ are located at the demarcation between the apical and baso-lateral domains of the plasma membrane in epithelial cells. TJ fulfill two major roles: (i) TJ prevent the mixing of membrane components; and (ii) TJ regulate the selective paracellular permeability. Disruption of TJ is regarded as one of the earliest hallmarks of epithelial injury, leading to the loss of cell polarity and tissue disorganization. Many factors have been identified as modulators of TJ assembly/disassembly. More specifically, in addition to its role as an energy sensor, adenosine monophosphate-activated protein kinase (AMPK) participates in TJ regulation. AMPK is a ubiquitous serine/threonine kinase composed of a catalytic α-subunit complexed with regulatory β-and γ-subunits. AMPK activation promotes the early stages of epithelial TJ assembly. AMPK phosphorylates the adherens junction protein afadin and regulates its interaction with the TJ-associated protein zonula occludens (ZO)-1, thereby facilitating ZO-1 distribution to the plasma membrane. In the present review, we detail the signaling pathways up-and down-stream of AMPK activation at the time of Ca2+-induced TJ assembly.
Highlights
The correct establishment and maintenance of cell-cell contacts and cell polarity in multicellular organisms are crucial for normal cell physiology and tissue homeostasis [1,2]
Immunoprecipitation, with or without AICAR during a Ca2+ switch, revealed an enhanced interaction between these two proteins after Ca2+-switch and even more in the case of AICAR exposure. These results suggested that AMP‐activated protein kinase (AMPK) activation might facilitate tight junctions (TJ) assembly by phosphorylating afadin and inducing its association with zonula occludens (ZO)-1
This study found that the pharmacological inhibition of Calmodulin Kinase Kinase (CaMKK) or the direct inhibition of AMPK by Compound-C hampered AMPK phosphorylation and ZO-1 relocation to the TJ during a Ca2+ switch in MDCK cells, whereas the inactivation of LKB1 by shRNA did not significantly influence these processes [118]
Summary
The concept of TJ ( known as zonula occludens) emerged in 1963 with Farquhar and Palade’s experiments demonstrating, by electron microscopy, the regular occurrence in various rat and pig epithelia of a characteristic junctional complex whose components bear a relationship to each other and to the lumen of the organ [18]. TJ prevent membrane proteins from diffusing freely between the two membrane compartments This function is absolutely required in order for apical and basolateral domains to maintain their distinct lipid and protein compositions [23]. They create a physiological and structural paracellular barrier that regulates the selective passage and exchange of molecules [24,25,26,27]. The selective passage of these components through TJ is mediated by aqueous pores whose structures have yet to be fully defined [28] In addition to these functions, TJ are connected to signaling pathways that communicate with the cell cytoplasm and subcellular components [29]. To be able to perform all of these diverse functions, TJ must possess a complicated architecture based upon a multiprotein complex that is composed of more than 40 proteins that are classified either as transmembrane proteins or as cytoplasmic proteins bound to the actin cytoskeleton [30] (Figure 1)
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