[Frontiers in Bioscience 14, 2115-2129, January 1, 2009]
Rab family small G proteins in regulation of epithelial apical junctions
Noriyuki Nishimura, Takuya Sasaki
Department of Biochemistry, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
TABLE OF CONTENTS
1. ABSTRACT
Tight junctions (TJs) and adherens junctions (AJs) comprise epithelial apical junctions that adhere neighboring epithelial cells and determine tissue organization. They are highly dynamic structures that undergo continuous remodeling during physiological morphogenesis and under pathological conditions. The assembly and disassembly of epithelial apical junctions is regulated by the interplay between a variety of cellular processes, such as the remodeling of actin cytoskeletons and the endocytic recycling of apical junctional proteins, and coordinated by many signaling pathways. Accumulating evidences demonstrate that Rab family small G proteins are crucially involved in the regulation of epithelial apical junctions. Rab proteins localized both at endosomes and apical junctions can influence the assembly and disassembly of epithelial apical junctions. In this review, we summarize how Rab proteins influence epithelial apical junctions and describe the role of Rab8/13-a junctional Rab13-binding protein (JRAB)/molecule interacting with CasL-like 2 (MICAL-L2) complexes in the regulation of epithelial apical junctions.
2. INTRODUCTION
Rab family small G proteins are first identified as evolutionarily conserved, essential regulators of membrane traffic in the 1980s (1-3). They are members of the wider Ras superfamily of small G proteins and appear to control a variety of cellular processes ranging from membrane traffic to membrane-cytoskeleton interactions and signal transduction (4, 5). To date, over 70 Rab and Rablike proteins have been identified in human, and several Rab proteins are implicated in the assembly and/or disassembly of epithelial apical junctions (Figure 1) (6). Epithelial apical junctions defined by tight junctions (TJs) and adherens junctions (AJs) provide important adhesive contacts between neighboring epithelial cells and crucially determine tissue organization both in health and disease (7). They are very dynamic cellular structures that are continuously remodeled and control the cellular morphogenesis and tissue patterning. It is not surprising that many signaling pathways and cellular processes regulate epithelial apical junctions. In this review, we first provide an overview of Rab proteins and epithelial apical junctions. Then we summarize how Rab proteins influence epithelial apical junctions and describe the role of Rab8/13-a junctional Rab13-binding protein (JRAB)/molecule interacting with CasL-like 2 (MICAL-L2) complexes in the regulation of epithelial apical junctions.
3. Rab FAMILY SMALL G PROTEINS
3.1. Activation/inactivation of Rab proteins
Rab proteins interconvert between active GTP-bound forms and inactive GDP-bound forms, and serve as membrane-associated molecular switches. This switch is controlled by guanine nucleotide exchange factor (GEF), which triggers the binding of GTP, and GTPase-activating protein (GAP), which accelerates hydrolysis of the bound GTP to GDP (8-10). Rab proteins associate tightly with membranes by virtue of their carboxyl terminal single or double geranylgeranylation and undergo a membrane association/dissociation cycle coupled with a GTP/GDP cycle. GDP dissociation inhibitor (GDI) binds to a geranylgeranylated Rab protein in its GDP-bound form, extracting it from the membranes and keeping it in the cytosol (11). The cytosolic Rab-GDI complex carries all of the information that is needed for the correct targeting of Rab proteins to membranes. GDI displacement factor (GDF) dissociates Rab proteins from the Rab-GDI complex and enables membrane attachment of Rab proteins (12-14). Once dissociated from GDI, Rab proteins are converted to their GTP-bound form by their specific GEFs. The active membrane-bound Rab proteins exert their variety of functions by binding to their specific effector proteins. After inactivation by their specific GAPs, the GDP-bound Rab proteins can be extracted from the membrane by GDI and recycled back to the cytosol.
A Rab effector protein responds to a specific Rab protein and mediates at least one element of its downstream effects (15). Rapidly growing list of Rab effector proteins has revealed that each Rab protein appears to signal through a variety of different effector proteins that together act to translate the signal from one Rab protein to several diverse aspects of cellular processes. Rab proteins contribute the specificity in membrane traffic by regulating budding, transport, tethering, and fusion steps in vesicular transport and by establishing membrane domains (16, 17). They also play important regulatory roles in membrane-cytoskeleton interactions by associating with molecular motors and other cytoskeleton-binding proteins (18, 19). In addition, they participate in the regulation of numerous signal transduction pathways (20, 21).
3.2. Rab proteins in membrane traffic
In vesicular transport, Rab proteins can control cargo collection during transport vesicle formation, enable motor proteins to interact with membranes to drive vesicle motility, and mediate the complex events of accurate tethering and fusion of transport vesicles with their target membranes (15). Rab9 effector TIP47 binds to GTP-bound Rab9 and increase its affinity for mannose 6-phosphate receptor (M6PR), facilitating the capture of M6PR into Rab9-positive transport carrier vesicles (22). GTP-bound Rab6 binds to the microtubule motor Rabkinesin-6 and promotes the delivery of vesicles from the Golgi to endoplasmic reticulum (23). A long coiled-coil tethering factor p115 that tethers endoplasmic reticulum-derived vesicles to the Golgi is identified as a Rab1 effector protein (24). GTP-bound Rab5 recruits another long coiled-coil tethering factor EEA1 onto early endosome, and the interaction of EEA1 with the soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor (SNARE) protein Syntaxin13 is required for homotypic early endosome fusion (25).
Rab protein is localized to the distinct subcellular membrane compartment and each compartment has a unique set of Rab proteins, which can serve as markers of the particular compartment (26, 27). For instance, Rab1 is on endoplasmic reticulum, Rab6 is on the Golgi, and Rab3 is on secretory granules and synaptic vesicles. Although the molecular mechanisms controlling Rab localization are not fully understood, the correct targeting of Rab proteins to their specific membranes is intimately linked to their activation. Rab proteins also contribute to establish specific membrane domains, which are well-characterized in the endocytic pathway (16, 17). Early endosomes harbor only Rab5 or a combination of Rab4 and Rab5, whereas recycling endosomes carry distinct domains of Rab4 and Rab11. Rab7 and Rab9 similarly share late endosomes. Rab5 GEF Rabex5 activates Rab5 on early endosomes and activated Rab5 interacts with Rab5 effector Rabaptin5 that in turn binds to Rabex5 and increases the exchange activity of Rabex5 on Rab5 (28-30). This Rabex5-Rab5-Rabaptin5 complex serves as a positive feedback loop to establish a Rab5-domain on early endosomes. Importantly, the Rab5-containing early endosomes can be converted into Rab7-containing late endosomes. This conversion is mediated by the six subunits class C homotypic fusion and vacuole protein sorting (HOPS)/vacuole protein sorting (VPS) complex that contains a Rab5 effector hVps11 and a Rab7 GEF hVps39 (31). The coupling of a downstream Rab GEF with an upstream Rab effector could be a way to achieve specificity in membrane traffic (32).
3.3. Rab proteins in membrane-cytoskeleton interactions
In addition to myosin and kinesin motor proteins, Rab proteins also interact with non-motor cytoskeleton-binding proteins directly or via an intermediary protein, and control membrane-cytoskeleton interactions (18, 19). These non-motor cytoskeleton-binding proteins include alpha-actinin, EB1, and Hook1. Rab3 effector Rabphilin3 binds to actin cytoskeletons in an alpha-actinin-dependent manner and facilitates the vesicle-F-actin network interactions below the plasma membrane (33, 34). Rab27 effector Melanophilin, which links Rab27 to myosin Va on melanosome, also interacts with microtubule plus-end tracking protein EB1 (35). A microtubule-binding protein Hook1 physically associates with endocytic Rab7, Rab9 and Rab11 as well as membranes, and the Drosophila homologue of Hook1 regulates the membrane traffic of internalized ligands to late endosomes (36, 37).
3.4. Rab proteins in signal transduction
Rab proteins are increasingly found downstream of signal transduction pathways that direct a variety of cellular processes, including gene expression, cell survival, cell growth, differentiation, proliferation, cell cycle, and apoptosis. Rab4 is phosphorylated by the mitotic Cdk1 kinase and participates in the control of the endosomal compartment during mitosis (38). GTP-bound Rab8 interacts with a member of germinal center kinases (GCKs) that regulate eukaryotic stress responses (39). GTP-bound Rab11 associates with phosphatidylinositol 4-kinase beta (PI4Kbeta) that is implicated in the endocytic recycling and activation of extracellular signal-regulated kinase 1/2 (ERK1/2) (40, 41).
4. EPITHELIAL APICAL JUNCTIONS
TJs and AJs are located at the apical end of the basolateral membrane, and define the organization of epithelial apical junctions (7). Whereas TJs seal the intercellular space and delineate the boundaries between the apical and basolateral membranes, AJs principally initiate and maintain cell-cell contacts. Both TJs and AJs are built according to the same architectural principle as other adhesion complexes. A set of different transmembrane proteins mediates cell-cell adhesion and is linked to cytosolic plaque proteins that anchor the junction to the cytoskeleton. At TJ, the principal transmembrane proteins forming the paracellular diffusion barrier are claudins that comprise claudin family consisting of at least 24 members in mammalian cells (42-44). Other transmembrane proteins identified at TJ include occludin, tricellulin, junction adhesion molecules (JAMs), coxsackievirus and adenovirus receptor (CAR), and Crumb3 (CRB3). Occludin is the first identified transmembrane protein at TJs, whose physiological function remains to be established (45). Tricellulin is recently identified as another TJ component specifically localized to the tricellular junctions (46). JAMs consist of at least 5 JAM family members and the first JAM to be identified, JAM-A, is involved in the accumulation of a cell polarity protein complex, the Par3/Par6/atypical protein kinase C (aPKC) complex, at TJ (47-49). CAR associates with JAM-C and mediates attachment and infection by group B coxsackieviruses (CVB) and adenoviruses (50). CRB3 forms another cell polarity protein complex, the CRB3/PALS1/PATJ complex (51). At AJ, the transmembrane protein, E-cadherin, forms the characteristic structures of AJs (52). E-cadherin is a member of cadherin superfamily that comprises more than 100 members, each of which is expressed in non-epithelial cells as well as in epithelial cells (53). Nectins are identified as additional transmembrane proteins at AJ and involved in the organization of AJ either in cooperation with or independently of E-cadherin (54). These transmembrane proteins are associated with TJ and AJ plaque proteins in the cytosol, which form an organizing platform for a variety of scaffolding, signaling, and membrane traffic proteins, including zonula occludens (ZO) proteins (ZO-1, ZO-2, and ZO-3), membrane-associated guanylate kinase inverted (MAGI) proteins (MAGI-1, MAGI-2, and MAGI-3), catenins, the Par3/Par6/aPKC and CRB3/PALS1/PATJ complexes, Rab3B, Rab8, Rab13, and Rab34 (55-57).
5. ENDOCYTIC RECYCLING PATHWAYS IN EPITHELIAL CELLS
Endocytosis regulates the entry of small and large extracellular molecules into cells, and is multistep process involving the budding of plasma membrane and the formation of vesicles followed by their delivery and fusion with specific intracellular compartments (58, 59). Endocytosis can be divided into phagocytosis, which is the uptake of particles, and pinocytosis, which is the uptake of fluid. Furthermore, there are four basic mechanisms for pinocytosis: macropinocytosis, clathrin-dependent endocytosis, caveolin-dependent endocytosis, and clathrin- and caveolin-independent endocytosis. Whereas the formation of large actin-coated vacuolae are responsible for macropinocytosis, the polymerization of a specific coat protein clathrin and the invagination of caveolin-containing cholesterol-enriched microdomains drive clathrin-dependent and caveolin-dependent endocytosis, respectively. There are several clathrin- and caveolin-independent endocytosis pathways that can be further classified based on the requirement for dynamin and the involvement of Cdc42, RhoA, and ARF6 (59).
Most cargo molecules internalized from plasma membrane are delivered to early endosome, which consists of two spatially separated populations of apical and basolateral early endosomes (AEE and BEE) in polarized epithelial cells. Whereas some internalized molecules in basolateral early endosome may directly return to basolateral membrane, internalized molecules in apical and basolateral early endosomes eventually merge in a tubulovesicular compartment. This compartment is variously termed apical recycling endosome (ARE), common endosome (CE), or subapical compartment (SAC), and serves as a sorting station that determines the fate of internalized molecules (60). Subsequently, they may enter recycling endosome to return to plasma membrane, or be degraded in late endosome and lysosomes (Figure 1).
Endosomal recycling vesicles containing the internalized cargo molecules are eventually fused with plasma membrane, which is catalyzed by SNARE proteins (61). They have over 30 members resided at distinct subcellular compartments in mammalian cells and functionally can be classified into 'v-SNARE' on the vesicle and 't-SNARE' on the target membrane. Specific interaction of v-SNARE with the cognate t-SNARE forms a SNARE complex that drives membrane fusion. In polarized epithelial cells, two major t-SNARE proteins, Syntaxin3 and Syntaxin4, are spatially segregated into different plasma membrane domains with the apical membrane-confined Syntaxin3 and basolateral membrane-confined Syntaxin4 (62). Whereas the apical targeting requires the tetanus neurotoxin (TeNT)-resistant v-SNARE TI-VAMP (VAMP7), the basolateral targeting involves the TeNT-sensitive v-SNARE cellubrevin (VAMP3) (63, 64).
Before the SNARE-dependent fusion reaction, endosomal recycling vesicles need to be tethered with plasma membrane. Whereas SNARE proteins on opposing membrane bring the two membranes into very close apposition for membrane fusion, tethering factors physically link the two membranes at some distances with a degree of reversibility. Central to the tethering of vesicles with plasma membrane is Rab proteins and a large octameric complex called the exocyst (65). The exocyst is composed of Sec3, Sec5, Sec6, Sec8, Sec10, Sec15, Exo70, and Exo84, and associated with the apical junctions and recycling endosome in polarized epithelial cells. It interacts with several known regulators of epithelial apical junctions such as Ral, ARF6, and Rab11, and functions in the endocytic recycling as well as the basolateral membrane transport (66, 67).
6. ASSEMBLY AND DISASSEMBLY OF EPITHELIAL APICAL JUNCTIONS
Epithelial cells are very plastic and remodel intercellular junctions even within apparently stable, confluent cultured monolayers (68, 69). To assemble or disassemble epithelial apical junctions, epithelial cells need to regulate the functions of apical junctional proteins at the cell-surface. The remodeling of actin cytoskeletons and the endocytic recycling of apical junctional proteins provide important molecular mechanisms. Failure in this regulation is manifested in a variety of diseases, such as tissue fibrosis and tumor invasion/metastasis (70).
The role of actin cytoskeleton in the assembly and maintenance of epithelial apical junctions is demonstrated by the fact that actin-disrupting pharmacological agents such as cytochalasin D and latrunculin A rapidly and efficiently disrupt epithelial apical junctions (71, 72). During the assembly of epithelial apical junctions, the formation of E-cadherin-mediated contacts triggers remodeling of actin cytoskeletons, and their maturation is accompanied by the assembly of a circumferential actin belt and TJs. Although the established model of E-cadherin-mediated AJ formation predicts a stable link between the E-cadherin-beta-catenin complex and the actin cytoskeleton that is mediated by alpha-catenin, the recent data shows that alpha-catenin does not stably couple E-cadherin to the circumferential actin belt, but can directly regulates actin-filament organization by suppressing Arp2/3-mediated actin polymerization (73, 74).
Whereas apical junctional proteins exist predominantly at the cell-surface under basal conditions, their endosomal pools can be detected in a variety of cellular contexts (75-77). For endocytosis of apical junction proteins, four distinct pathways have been revealed. These include macropinocytosis in IFN-gamma-treated human colorectal cancer T84 cells (78) and CVB-exposed human colon epithelial Caco2 cells (57), clathrin-dependent endocytosis in confluent kidney epithelial MDCK cells (79), Ca2+-depleted T84 cells (80), AJ-enriched fraction of rat liver (81), caveolin-dependent endocytosis in Ca2+-depleted SCC12f keratinocytes (82), Escherichia coli cytotoxic necrotizing factor-1-treated T84 cells (83), actin-depolymerized MDCK cells (84), and clathrin-independent endocytosis in isolated human breast cancer MCF7 cells (85). Internalized apical junction proteins are also detected in multiple sites including Rab5-positive early endosomes (79), Rab11-positive recycling endosomes (78, 83, 86), Rab7-positive late endosomes (87), Rab13-positive vesicles (88), Syntaxin4-positive compartments (80), and Syntaxin3-positive vacuolar apical compartments (89). Although the endocytosed proteins in Rab7-positive late endosomes are likely targeted to lysosomal degradation, they are recycled from these compartments back to the plasma membrane.
A recent genome-wide RNA interference screen for genes required for endocytic recycling in Caenorhabditis elegans provides further evidence that the endocytic recycling is essential for the regulation of epithelial apical junctions. This screen identifies the cell polarity proteins, Par3, Par6, aPKC, and Cdc42, which direct the formation and maturation of apical junctions and cell polarity in epithelial cells. The perturbation of Par6 or Cdc42 function inhibits the endocytic recycling both in Caenorhabditis elegans coelomocytes and human HeLa cells (90). Furthermore, the endocytosis of E-cadherin is recently proposed as the driving force to dissociate the stable E-cadherin-E-cadherin interactions and thereby disassemble epithelial apical junctions based on the observations that maneuvers inhibiting E-cadherin endocytosis also prevent the disassembly of E-cadherin-E-cadherin interactions. This contrasts with the current model, in which the circumferential actin belt mediates the clustering and stabilization of the weak E-cadherin-E-cadherin interactions between two opposing plasma membranes and then assembles epithelial apical junctions (81, 91-93). Although these disparate models remain to be resolved, both models emphasize the close functional and mechanistic relationship between the E-cadherin-E-cadherin interactions and the E-cadherin endocytosis. The current model suggests that the free E-cadherin, rather than the bound E-cadherin engaged in adhesion, undergoes endocytosis and the E-cadherin-E-cadherin interactions prevent E-cadherin endocytosis, perhaps by activating Rac1 signaling and remodeling the actin cytoskeleton (81, 93). In contrast, the new model implies that endocytosis targets the bound E-cadherin engaged in adhesion, rather than the free E-cadherin (91, 92).
7. Rab PROTEINS IMPLICATED IN REGULATION OF EPITHELIAL APICAL JUNCTIONS
7.1. Rab3B
Although Rab3 subfamily proteins (Rab3A, Rab3B, Rab3C, and Rab3D) are enriched in neuronal/secretory cells and control the regulated exocytosis through the interaction with Rab3 effector proteins, Rabphilin3, Rim1/2, and Noc2, Rab3B expression is also detected in other cells (4). In epithelial cells, Rab3B is recruited to TJ upon cell-cell contact formation and involved in the transport of polymeric immunoglobulin receptor (94, 95). Rab3B also regulates the reorganization of actin cytoskeleton and the targeting of ZO-1 to the plasma membrane through a process, in which phosphatidylinositol 3-kinase (PI3K) is involved, in neuroendocrine PC12 cells (96).
7.2. Rab4
Rab4 is localized predominantly to early endosome and, to a lesser extent, to recycling endosome and thought to be mainly involved in recycling from early endosome to plasma membrane. In Sertoli cells, Rab4 associates with alpha- and beta-catenins as well as with actin cytoskeletons and is involved in the disassembly of a testis-specific F-actin-based junctional structure, "ectoplasmic specialization", that shares features of TJ, AJ, and focal adhesion (FA) (97). In fibroblasts, Rab4 also regulates cell-extracellular matrix interactions by controlling the PDGF-dependent recycling of alphavbeta3 integrin through the interaction with Rab4 effector Rabip4 (98, 99).
7.3. Rab5
Rab5 is a key regulator of the transport from plasma membrane to early endosomes and also implicated in the macropinocytosis (100, 101). In CVB-exposed Caco2 cells, Rab5 and its effector Rabankyrin5 regulate the endocytosis of occludin (57). Rab5 activation is involved in the hepatocyte growth factor (HGF)/scatter factor (SF)- or 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced disruption of cell-cell adhesion and subsequent cell migration through co-endocytosis of E-cadherin and c-Met in MDCK cells (102, 103). In HGF/SF-stimulated MDCK cells, Rab5 activation is mediated by the sequential action of c-Met, Ras, and Rab5 GEF RIN2 (104). In v-Src-induced epithelial to mesenchymal transitions (EMT), Rab5 activation also mediates the lysosomal targeting of E-cadherin (105). During zebrafish gastrulation, Rab5 controls the Wnt11-dependent endocytosis of E-cadherin and the cohesion of mesendodermal cells. (106). In Drosophila epithelial cells, loss of Rab5 results in the cellular accumulation of a cell polarity protein CRB (107).
7.4. Rab8
Rab8 is localized to the trans-Golgi network (TGN), recycling endosome, cytosolic vesicular structures, membrane protrusions, and primary cilia, and implicated in the polarized membrane traffic to the dendritic membrane, the actin-dependent movement of melanosomes, and the formation of membrane protrusions and primary cilia (108-115). Rab8 associates with MyosinVb (116), Optineurin-myosin VI (117), Rab8 GEF Rabin8 (118), JRAB/MICAL-L2 (119), Optineurin-huntingtin (120), and cenexin/Odf2 (121), and connected to actin and microtubule cytoskeletons. Recently, Rab8 is linked to two human diseases, microvillus inclusion disease and Bardet-Biedle syndrome, which shows the shortening of microvilli in intestinal epithelial cells and the primary cilia dysfunction, respectively (114, 122).
Rab8 is also involved in cell-cell adhesion during Dictyostelium discoideum development, and associates with E-cadherin as well as actin cytoskeletons in Sertoli cells (123, 124). In epithelial cells, Rab8 is shown to mediate the epithelial-specific adaptor protein complex AP-1B-dependent basolateral transport (117, 120, 125). Although E-cadherin is initially recognized as an AP-1B-independent basolateral cargo (126, 127), it is recently linked to AP-1B through the interaction with phosphatidylinositol-4-phosphate 5-kinase gamma (PIP5Kgamma) (128). Consistent with this, Rab8 associates with JRAB/MICAL-L2 and is involved in E-cadherin transport (119).
7.5. Rab11
Rab11 is distributed across a variety of post-Golgi membranes, but serves as the most prominent recycling endosome marker. Rab11 interacts with a component of the exocyst Sec15, and is implicated in regulating the post-Golgi traffic (129). In Drosophila epithelial cells, E-cadherin accumulates in Rab11-positive recycling endosomes upon inactivation of components of the exocyst Sec5, Sec6, and Sec15 (130). Rab11 also interacts with the same effector proteins FIP3/arfophilin-1and FIP4/arphophilin-2 as ARF6, a key regulator for the endocytic recycling of E-cadherin, and controls the transport of E-cadherin from the TGN to basolateral membranes via an intermediate compartment, Rab11-positive recycling endosome, in epithelial cells (131, 132).
7.6. Rab13
Whereas Rab13 associates with vesicles throughout the cytosol in fibroblasts, it accumulates at TJ in polarized epithelial cells and is recruited to cell-cell contacts from a cytosolic pool at an early stage of junctional complex assembly (133, 134). Rab13 mediates the endocytic recycling of occludin and is implicated in the assembly of functional TJs in epithelial cells (88, 135). Rab13 also regulates the scattering of MDCK cells in response to TPA, the neurite outgrowth, and the regeneration of neurons (136-138). cGMP phosphodiesterase delta subunit (delta-PDE), protein kinase A (PKA), and JRAB/MICAL-L2 have been identified as Rab13-binding proteins. delta-PDE exhibits two putative carboxyl PDZ binding motifs and regulates the membrane association and disassociation of Rab13 (139). GTP-bound Rab13 interacts directly with PKA and inhibits the PKA-dependent phosphorylation and TJ recruitment of vasodilator-stimulated phosphoprotein (VASP) (140, 141).
7.7. Rab34
Rab34 is localized to the Golgi, membrane ruffles, and macropinosome in fibroblasts (142, 143), and associated with the TJ and cytosolic vesicles containing caveolin in epithelial cells (57). Whereas Rab34 is implicated in the formation of membrane ruffles and macropinocytosis in fibroblasts (143), its activity is required for the CVB-induced endocytosis of occludin in Caco2 cells (57). In contrast to IFN-gamma that triggers macropinocytosis of JAM, occludin, and claudins (78), CVB induces macropinocytosis of occludin without affecting the localization of other TJ membrane proteins (57). In CVB-exposed Caco2 cells, activated Rab34 facilitates the constitutive occludin endocytosis downstream of Ras.
7.8. Rab8/13-JRAB/MICAL-L2 complex
MICAL is originally identified as a novel binding protein of CasL/HEF1/NEDD9 that regulates the scattering of epithelial cells and the progression and metastasis of cancer cells (144, 145). Now it belongs to a MICAL family consisted of five members (MICAL-1, MICAL-2, MICAL-3, MICAL-L1, and JRAB/MICAL-L2) in mammals and two members (D-MICAL and D-MICAL-L) in Drosophila (146). MICAL family proteins are large, multidomain, cytosolic proteins expressed in specific neuronal and non-neuronal cells both during development and in adulthood. They contain calponin homology (CH), LIM, and coiled-coil (CC) domains. MICAL-1, MICAL-2, MICAL-3, and D-MICAL also possess a flavin-adenine dinucleotide (FAD)-binding monooxygenase domain. Members of MICAL family proteins are shown to associate with Semaphorin receptor Plexin, Rab1, vimentin, and microtubule, and implicated in the invasive growth (144, 146-149). MICAL-1, MICAL-2, MICAL-3, and D-MICAL function downstream of Semaphorin receptor Plexin in axon guidance (146, 150). MICAL-2 isoforms (PVa and PVb) are involved in the progression of prostate cancer (151). JRAB/MICAL-L2 plays a role in the scattering of MDCK cells in response to TPA (136).
JRAB/MICAL-L2 is originally identified as a Rab13 effector protein that mediates the endocytic recycling of occludin and the formation of functional TJs (152). It is resided in recycling endosome, cytosolic vesicular structures, and plasma membrane, and is also associated with actin cytoskeletons and localized to TJs in epithelial cells and distributed along stress fibers in fibroblasts (152). JRAB/MICAL-L2 also interacts with both Rab8 and Rab13 via its carboxyl-terminal region with CC domain. Is there any difference between the Rab8-JRAB/MICAL-L2 and Rab13-MICAL-L2 complexes? Rab8 and Rab13 compete with each other for the binding to JRAB/MICAL-L2 and form the two distinct JRAB/MICAL-L2 complexes within a cell. Whereas Rab8, Rab13, and JRAB/MICAL-L2 are all localized to recycling endosome, cytosolic vesicular structures, and plasma membrane, JRAB/MICAL-L2 interacts with Rab8 and Rab13 at the distinct sites. JRAB/MICAL-L2 shows a closer relationship with Rab8 at recycling endosome and with Rab13 at plasma membrane, respectively (Figure 2). Whereas JRAB/MICAL-L2 regulates the transport of claudins, occludin, and E-cadherin, Rab13 specifically mediates the transport of claudins and occludin but not E-cadherin, and Rab8 controls the Rab13-independent transport of E-cadherin. JRAB/MICAL-L2 regulates the Rab8-dependent E-cadherin transport at perinuclear recycling/storage compartments (PNC) and the Rab13-dependent claudins and occludin transport at plasma membrane, respectively (Figure 3) (119).
Although an increasing number of Rab effector proteins are reported to interact with closely related multiple Rab proteins (153), JRAB/MICAL-L2 is a novel type of Rab effector proteins that associate with multiple Rab proteins forming mutually exclusive complexes. In order to ensure the specificity in membrane traffic, the action of each Rab protein needs to be coordinated with other Rab proteins (32). The Rab coupling is potentially mediated by Rab-binding proteins that can interact with multiple Rab proteins. Three types of these Rab-binding proteins are currently identified. First type functions as an effector protein for one Rab protein and as a GEF for another Rab protein. The identification of Sec2 and the class C-VPS/HOPS complex as this type of Rab-binding proteins leads to a "Rab cascade" concept (31, 154). Second type is a divalent Rab effector protein that binds simultaneously to two Rab proteins associated with compartments in dynamic continuity. Rabaptin5, Rabenosyn5, and Rabip4' are able to interact simultaneously with Rab4 and Rab5, and are likely involved in the coordination of the endocytic recycling pathway as well as the organization of Rab4 and Rab5 domains on endosomal membranes (155-157). Third type is a Rab effector protein that associates with multiple Rab proteins in a mutually exclusive manner. JRAB/MICAL-L2 is a shared Rab effector protein that forms mutually distinct complexes with Rab8 and Rab13 and coordinates the assembly of epithelial apical junctions (119).
8. SUMMARY AND PERSPECTIVES
Epithelial apical junctions control paracellular fluxes and membrane polarity, and encompass a platform for regulatory and signaling proteins that establishes the epithelial phenotype. Their function is determined by, and regulated through, a variety of cellular processes. In this review, we focused the endocytic recycling of apical junctional proteins and highlight the role of Rab proteins. Although it is becoming increasingly clear that several Rab proteins are critically involved in the regulation of epithelial apical junctions, the relation and coordination of each Rab proteins remain elusive. We have described that JRAB/MICAL-L2 coordinated the Rab8-dependent AJ protein traffic and the Rab13-dependent TJ protein traffic. Of course, the Rab8/13-JRAB/MICAL-L2 complexes are not the only processes. Further studies are required to elucidate their interplay with other cellular processes such as surface clustering of apical junctional proteins, cytoskeletal activity, and cell signaling. As Rab8 is recently linked to two human diseases, microvillus inclusion disease and Bardet-Biedle syndrome (114, 122), studies of the Rab8/13-JRAB/MICAL-L2 complexes will contribute to understand how epithelial cells establish their own phenotypes in physiological and pathological conditions.
9. ACKNOWLEDGEMENTS
We thank past and present members of our laboratory for participating in this study. This study was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, Culture, and Technology of Japan.
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Abbreviations: TJ: tight junction, AJ: adherens junction, JRAB: a junctional Rab13-binding protein, MICAL-L2: molecule interacting with CasL-like 2, GEF: guanine nucleotide exchange factor, GAP: GTPase-activating protein, GDI: GDP dissociation inhibitor, GDF: GDI displacement factor, M6PR: mannose 6-phosphate receptor, SNARE: soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor, HOPS: homotypic fusion and vacuole protein sorting, VPS: vacuole protein sorting, JAM: junction adhesion molecule, CAR: coxsackievirus and adenovirus receptor, CRB: Crumb, aPKC: atypical protein kinase C, CVB: group B coxsackieviruses, FA: focal adhesion, HGF: hepatocyte growth factor, SF: scatter factor, TPA: 12-O-tetradecanoylphorbol-13-acetate, TGN: trans-Golgi network, delta-PDE: cGMP phosphodiesterase delta subunit, PKA: protein kinase A, CC: coiled-coil.
Key Words: Rab8, Rab13, JRAB, MICAL-L2, Apical Junction, Endocytic Recycling, Review
Send correspondence to: Takuya Sasaki, Department of Biochemistry, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan, Tel: 81-88-633-9223, Fax: 81-88-633-9227, E-mail:sasaki@basic.med.tokushima-u.ac.jp