Kegg Pathway: Adherens junction

Nat Cell Biol. 2008 Jul 20;
Shaye DD, Casanova J, Llimargas M

Through intercalation, a fundamental mechanism underlying elongation during morphogenesis, epithelial cells exchange places in a spatially oriented manner. Epithelial cells are tightly coupled through distinct intercellular junctions, including Adherens junctions. Whether trafficking-mediated regulation of adhesion through Adherens junctions modulates intercalation in vivo remains controversial. In Drosophila melanogaster, cells in most branches intercalate during tracheal development. However, Wingless (Wg)-promoted expression of the transcription factor Spalt (Sal) in the dorsal trunk inhibits intercalation by an unknown mechanism. Here we have examined the role of trafficking in tracheal intercalation and show that it requires endocytosis, whereas it is opposed by Rab11-mediated recycling in the dorsal trunk. Subapical Rab11 accumulation is enhanced by sal and elevated Rab11-mediated recycling occurs in the dorsal trunk, suggesting that upregulation of Rab11 is one way in which sal inhibits intercalation. We found that dRip11, which regulates Rab11 localization and function, is regulated by sal and can modulate intercalation. Finally, we provide evidence that levels of E-cadherin (DE-cad), an Adherens junction component and Rab11-compartment cargo, are dynamically regulated by trafficking during tracheal development, and that such regulation modulates intercalation. Our work suggests a mechanism by which trafficking of adhesion molecules regulates intercalation, and shows how this mechanism can be modulated in vivo to influence cell behaviour.

Blood. 2008 Jul 18;
Alcaide P, Newton G, Auerbach S, Sehrawat S, Mayadas TN, Golan DE, Yacono P, Vincent P, Kowalczyk A, Luscinskas FW

Vascular Endothelial-Cadherin (VE-cad) is localized to Adherens junctions at endothelial cell borders and forms a complex with alpha-, beta-, gamma- and p120-catenins (p120). We previously showed that the VE-cad complex disassociates to form short-lived "gaps" during leukocyte transendothelial migration (TEM)(1); however, whether these gaps are required for leukocyte TEM is not clear. Recently p120 has been shown to control VE-cad surface expression by endocytosis. We hypothesized that p120 regulates VE-cad surface expression, which would in turn have functional consequences for leukocyte transmigration. Here we show that endothelial cells transduced with an adenovirus expressing p120GFP fusion protein significantly increases VE-cad expression. Moreover, endothelial junctions with high p120GFP expression largely prevent VE-cad gap formation and neutrophil leukocyte TEM; if TEM occurs, the length of time required is prolonged. We find no evidence that VE-cad endocytosis plays a role in VE-cad gap formation and instead show that this process is regulated by changes in VE-cad phosphorylation. In fact, a non-phosphorylatable VE-cad mutant prevented TEM. In summary, our studies provide compelling evidence that VE-cad gap formation is required for leukocyte transmigration and identify p120 as a critical intracellular mediator of this process through its regulation of VE-cad expression at junctions.

Biochem J. 2008 Jul 17;
Menzel N, Melzer J, Waschke J, Lenz CE, Wecklein H, Lochnit G, Drenckhahn D, Raabe T

Phosphorylations by tyrosine and serine/threonine kinases regulate the interactions between components of the cadherin/catenin cell adhesion complex and thus can influence the dynamic modulation of cell adhesion under normal and disease conditions. Previous mutational analysis and localization experiments suggested an involvement of single members of the family of p21-activated kinases (PAKs) in the regulation of cadherin mediated cell adhesion, but the molecular mechanism remained elusive. We addressed this question using the Drosophila PAK protein Mbt, which is most similar to vertebrate PAK4. Previous phenotypic analysis showed that Mbt has a function to maintain Adherens junctions during eye development and indicated a requirement of the protein in regulation of the actin cytoskeleton and the cadherin/catenin complex. Here we show that activation of Mbt leads to destabilization of the interaction of the Drosophila beta-catenin homologue Armadillo with DE-cadherin resulting in a decrease in DE-cadherin mediated adhesion. Two conserved phosphorylation sites in Armadillo were identified that mediate this effect. Our findings support the previous observation that activation of the human Mbt homologue PAK4 leads to anchorage independent growth and provide a functional link between a PAK protein and the cadherin-catenin complex.

Kidney Int. 2008 Jul 16;
Eley L, Gabrielides C, Adams M, Johnson CA, Hildebrandt F, Sayer JA

Joubert syndrome and related disorders are autosomal recessive multisystem diseases characterized by cerebellar vermis aplasia/hypoplasia, retinal degeneration and cystic kidney disease. There are five known genes; mutations of which give rise to a spectrum of renal cystic diseases the most common of which is nephronophthisis, a disorder characterized by early loss of urinary concentrating ability, renal fibrosis, corticomedullary cyst formation and renal failure. Many of the proteins encoded by these genes interact with one another and are located at Adherens junctions or the primary cilia and or basal bodies. Here we characterize Jouberin, a multi-domain protein encoded by the AHI1 gene. Immunohistochemistry with a novel antibody showed that endogenous Jouberin is expressed in brain, kidney and HEK293 cells. In the kidney, Jouberin co-localized with aquaporin-2 in the collecting ducts. We show that Jouberin interacts with nephrocystin-1 as determined by yeast-2-hybrid system and this was confirmed by exogenous and endogenous co-immunoprecipitation in HEK293 cells. Jouberin is expressed at cell-cell junctions, primary cilia and basal body of mIMCD3 cells while a Jouberin-GFP construct localized to centrosomes in subconfluent and dividing MDCK cells. Our results suggest that Jouberin is a protein whose expression pattern supports both the Adherens junction and the ciliary hypotheses for abnormalities leading to nephronophthisis.Kidney International advance online publication, 16 July 2008; doi:10.1038/ki.2008.377.

Eur J Immunol. 2008 Jul 16;
Pfeiffer F, Kumar V, Butz S, Vestweber D, Imhof BA, Stein JV, Engelhardt B

Lymph nodes are strategically localized at the interfaces between the blood and lymphatic vascular system, delivering immune cells and antigens to the lymph node. As cellular junctions of endothelial cells actively regulate vascular permeability and cell traffic, we have investigated their molecular composition by performing an extensive immunofluorescence study for Adherens and tight junction molecules, including vascular endothelium (VE)-cadherin, the vascular claudins 1, 3, 5 and 12, occludin, members of the junctional adhesion molecule family plus endothelial cell-selective adhesion molecule (ESAM)-1, platelet endothelial cell adhesion molecule-1, ZO-1 and ZO-2. We found that junctions of high endothelial venules (HEV), which serve as entry site for naive lymphocytes, are unique due to their lack of the endothelial cell-specific claudin-5. LYVE-1(+) sinus-lining endothelial cells form a diffusion barrier for soluble molecules that arrive at the afferent lymph and use claudin-5 and ESAM-1 to establish characteristic tight junctions. Analysis of the spatial relationship between the different vascular compartments revealed that HEV extend beyond the paracortex into the medullary sinuses, where they are protected from direct contact with the lymph by sinus-lining endothelial cells. The specific molecular architecture of cellular junctions present in blood and lymphatic vessel endothelium in peripheral lymph nodes establishes distinct barriers controlling the distribution of antigens and immune cells within this tissue.Supporting Information for this article can be found at http//www.wiley-vch.de/contents/jc_2040/2008/38140_s.pdf.

J Cell Sci. 2008 Jul 15;
Kishikawa M, Suzuki A, Ohno S

Atypical protein kinase C (aPKC) generally plays crucial roles in the establishment of cell polarity in various biological contexts. In mammalian epithelial cells, aPKC essentially works towards the transition of primordial spot-like Adherens junctions (AJs) into continuous belt-like AJs, also called zonula Adherens, lined with perijunctional actin belts. To reveal the mechanism underlying this aPKC function, we investigated the functional relationship between aPKC and myosin II, the essential role of which in epithelial-