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Review
. 2018 Oct 17;131(20):jcs221853.
doi: 10.1242/jcs.221853.

Regulation of actin-based apical structures on epithelial cells

Thaher Pelaseyed  1 , Anthony Bretscher  2
Affiliations
Review

Regulation of actin-based apical structures on epithelial cells

Thaher Pelaseyed et al. J Cell Sci. .

Abstract

Cells of transporting epithelia are characterized by the presence of abundant F-actin-based microvilli on their apical surfaces. Likewise, auditory hair cells have highly reproducible rows of apical stereocilia (giant microvilli) that convert mechanical sound into an electrical signal. Analysis of mutations in deaf patients has highlighted the critical components of tip links between stereocilia, and related structures that contribute to the organization of microvilli on epithelial cells have been found. Ezrin/radixin/moesin (ERM) proteins, which are activated by phosphorylation, provide a critical link between the plasma membrane and underlying actin cytoskeleton in surface structures. Here, we outline recent insights into how microvilli and stereocilia are built, and the roles of tip links. Furthermore, we highlight how ezrin is locally regulated by phosphorylation, and that this is necessary to maintain polarity. Localized phosphorylation is achieved through an intricate coincidence detection mechanism that requires the membrane lipid phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] and the apically localized ezrin kinase, lymphocyte-oriented kinase (LOK, also known as STK10) or Ste20-like kinase (SLK). We also discuss how ezrin-binding scaffolding proteins regulate microvilli and how, despite these significant advances, it remains to be discovered how the cell polarity program ultimately interfaces with these processes.

Keywords: Actin; Cell polarity; Cytoskeleton; ERM proteins; Microvilli; Stereocilia.

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Conflict of interest statement

Competing interestsThe authors declare no competing or financial interests.

Figures

Fig. 1.
Fig. 1.
Organization and regulation of stereocilia and microvilli. (A) Stereocilia of auditory hair cells are arranged in a staircase configuration. Actin bundles are assembled and stabilized through actin-binding proteins such as fimbrin, espin and fascin. Stereocilia of each row are connected to stereocilia of adjacent rows through tip links. Tip links require a ternary complex of Myo7a, USH1C (harmonin) and SANS that binds to the cadherin CDH23. CDH23 forms a heteromeric interstereociliary link with protocadherin PCDH15 on the adjacent stereocilium. The cytoplasmic region of PCDH15 interacts with the mechano-electrical transduction (MET) channels. Auditory stimulus causes deflection towards taller rows, which generates an influx of K+ and Ca2+ ions through the MET channels. (B) Microvilli covering the apical aspects of intestinal epithelial cells require heterotypic extracellular linkages that are mediated by the protocadherin PCDH24 and mucin-like protocadherin MLPCDH. By analogy with stereocilia, the cytoplasmic tail of PCDH24 binds the ternary complex of USH1C (harmonin), the SANS homolog ANKS4B and Myo7b. The actin cytoskeleton is assembled and stabilized by villin, espin and fimbrin.
Fig. 2.
Fig. 2.
Model for spatial control of ezrin phosphocycling required for microvilli formation. (A) Ezrin undergoes continuous cycles of local phosphorylation in the tip region of microvilli where LOK resides; this is followed by global dephosphorylation, most likely at the base of microvilli where the LOK concentration is lower, before ezrin cycles back to its active, phosphorylated form. (B) Model of the coincidence detection mechanism behind LOK-mediated phosphorylation of ezrin. (1) Inactive cytoplasmic ezrin is recruited to the first apical identity code PI(4,5)P2. Priming by PI(4,5)P2 results in lower affinity between the FERM domain and the CTD. (2) The CTD of the second apical identity code, LOK, binds in a a wedge-like manner between the FERM domain and the CTD of ezrin. (3) LOK kinase domain can now phosphorylate ezrin on T567. (4) Phosphorylated active ezrin adopts an open conformation that allows crosslinking of the plasma membrane to the underlying actin cytoskeleton. Adapted from Pelaseyed et al. (2017), where it was published under a CC BY 4.0 license (https://creativecommons.org/licenses/by/4.0/).
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