RhoGTPases, actomyosin signaling and regulation of the Epithelial Apical Junctional Complex

doi:10.1016/j.semcdb.2014.09.003

Seminars in Cell & Developmental Biology

Volume 36, December 2014, Pages 194-203

https://doi.org/10.1016/j.semcdb.2014.09.003 Get rights and content

Abstract

Epithelial cells form regulated and selective barriers between distinct tissue compartments. The Apical Junctional Complex (AJC) consisting of the tight junction (TJ) and adherens junction (AJ) control epithelial homeostasis, paracellular permeability and barrier properties. The AJC is composed of mutliprotein complexes consisting of transmembrane proteins that affiliate with an underlying perijunctional F-actin myosin ring through cytoplasmic scaffold proteins. AJC protein associations with the apical actin-myosin cytoskeleton are tightly controlled by a number of signaling proteins including the Rho family of GTPases that orchestrate junctional biology, epithelial homeostasis and barrier function. This review highlights the vital relationship of Rho GTPases and AJCs in controlling the epithelial barrier. The pathophysiologic relationship of Rho GTPases, AJC, apical actomyosin cytoskeleton and epithelial barrier function is discussed.

Introduction

Epithelial cells form selective and dynamic barriers that control movement of fluid and solutes between distinct tissue compartments. These properties are achieved by polarized organization of proteins in intercellular junctions that mediate cell–cell adhesion and control epithelial homeostasis. The tight junction (TJ) and the subjacent adherens junction (AJ) are collectively referred to as the Apical Junctional Complex (AJC). The AJC not only plays a pivotal role in regulating intercellular adhesion, but also in controlling paracellular movement of fluid and solutes, thereby helping to maintain distinct environments across polarized epithelia [1], [2].

Structural and signaling proteins in the AJC and the underlying apical actomyosin cytoskeleton control dynamic properties of the AJC. We provide a brief overview of proteins that constitute the AJC with a subsequent focus on signaling by Rho GTPase family members and actin-myosin dynamics that control epithelial barrier function.

Section snippets

Molecular structure and function of the Apical Junctional Complex

The cytoplasmic domains of AJC transmembrane proteins associate with underlying plaque proteins that provide a link to the actin cytoskeleton. Over a 100 proteins have been identified in the AJC that include scaffold proteins, kinases, phosphatases, small GTPases and their corresponding exchange and activating proteins, transcription factors, actin binding proteins and filamentous actin itself. Scaffold proteins containing domains such as PDZ, SH3, WW and GK that help to organize the protein

AJC and the perijunctional actomyosin cytoskeleton

The actin cytoskeleton consists of a dynamic network of filaments that is spatially organized to define and maintain cell morphology, regulate dynamics of cell proliferation, control cell motility and migration. The actomyosin cytoskeleton interacts with transmembrane proteins that anchor cells to the substrate and adjoining cells. Actin filaments are remodeled by regulated and reversible transition from globular monomeric actin (G-actin) to filamentous actin (F-actin). Additionally, F-actin

Rho GTPases

The Ras superfamily of GTPases comprises more than 150 human proteins that are grouped in 5 families: Ras, Rho, Rab, Ran and Arf [24]. The Rho family (Ras homologous) has at least 25 protein members. The most extensively characterized family members are the classical Rho proteins: RhoA, Rac and Cdc42 that not only play a central role in controlling actin-myosin dynamics, but are also involved in other biological processes including microtubule dynamics, gene transcription, cell cycle and

AJC regulation by the Rho family of GTPases

The field of Rho GTPase family member regulation of actin cytoskeletal dynamics blossomed in the early 90s after their first documentation by Alan Hall [48], [49], [50]. Subsequently in 1995 we reported that RhoGTPase control TJ function and perijunctional F-actin organization in polarized epithelial cells [51]. Many additional studies have further shed light on control of the AJC by Rho GTPases and the actomyosin cytoskeleton [52], [53]. Interestingly, a delicate balance of Rho activity is

Acknowledgments

We thank Dr. Andrei Ivanov for valuable comments on the review. The authors’ research is supported by the National Institutes of Health (Grants DK59888, DK055679 to AN).

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ReviewRhoGTPases, actomyosin signaling and regulation of the Epithelial Apical Junctional Complex

Abstract

Introduction

Section snippets

Molecular structure and function of the Apical Junctional Complex

AJC and the perijunctional actomyosin cytoskeleton

Rho GTPases

AJC regulation by the Rho family of GTPases

Acknowledgments

Prog Biophys Mol Biol

Prog Mol Biol Transl Sci

Curr Opin Cell Biol

J Ultrastruct Res

Cell

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

Cell

Cell

Curr Opin Cell Biol

Dev Cell

Curr Biol: CB

Dev Cell

J Biol Chem

Cell

Curr Biol: CB

Cell Signal

J Biol Chem

Biochim Biophys Acta

J Biol Chem

Cell

J Biol Chem

Brain Res

Gastroenterology

J Biol Chem

Junctional complexes in various epithelia

J Cell biol

Structure of tight junctions in epithelia with different permeability

Proc Natl Acad Sci U S A

Physiology and function of the tight junction

Cold Spring Harbor Perspect Biol

ZO proteins and redox-dependent processes

Antioxid Redox Signal

Zonula occludens-1 and -2 are cytosolic scaffolds that regulate the assembly of cellular junctions

Ann NY Acad Sci

ZO-2, a tight junction scaffold protein involved in the regulation of cell proliferation and apoptosis

Ann NY Acad Sci

Cingulin, paracingulin, and PLEKHA7: signaling and cytoskeletal adaptors at the apical junctional complex

Ann NY Acad Sci

Epithelial adhesive junctions

F1000prime Rep

Coupling assembly of the E-cadherin/beta-catenin complex to efficient endoplasmic reticulum exit and basal-lateral membrane targeting of E-cadherin in polarized MDCK cells

J Cell Biol

p120 catenin associates with kinesin and facilitates the transport of cadherin–catenin complexes to intercellular junctions

J Cell Biol

p120-catenin binding masks an endocytic signal conserved in classical cadherins

J Cell Biol

Nectin and afadin: novel organizers of intercellular junctions

J Cell Sci

Nonmuscle myosin-2: mix and match

Cell Mol Life Sci: CMLS

Organization of actin, myosin, and intermediate filaments in the brush border of intestinal epithelial cells

J Cell Biol

Nucleated polymerization of actin from the membrane-associated ends of microvillar filaments in the intestinal brush border

J Cell Biol

Increases in guinea pig small intestinal transepithelial resistance induced by osmotic loads are accompanied by rapid alterations in absorptive-cell tight-junction structure

J Cell Biol

Occluding junctions in cultured epithelial monolayers

Am J Physiol

Effects of cytochalasin D on occluding junctions of intestinal absorptive cells: further evidence that the cytoskeleton may influence paracellular permeability and junctional charge selectivity

J Cell Biol

Intestinal absorptive cell tight junctions are linked to cytoskeleton

Am J Physiol

The Ras superfamily at a glance

J Cell Sci

Rho family GTPases

Biochem Soc Trans

The Y-box factor ZONAB/DbpA associates with GEF-H1/Lfc and mediates Rho-stimulated transcription

EMBO Rep

Review
RhoGTPases, actomyosin signaling and regulation of the Epithelial Apical Junctional Complex