Pathway maps

Cell adhesion_Endothelial cell contacts by junctional mechanisms
Cell adhesion_Endothelial cell contacts by junctional mechanisms

Object List (links open in MetaCore):

VE-cadherin, Claudin-14, Occludin, Plakoglobin, p120-catenin, Claudin-5, Connexin 43, Connexin 40, N-cadherin, Cingulin, Claudin-5, N-cadherin, Connexin 43, JAM2, Plakophilin 4, Connexin 37, Desmoplakin, Occludin, ZO-2, Actin cytoskeletal, JAM1, Claudin-3, Beta-catenin, JAM1, Claudin-1, Connexin 40, ZO-1, MAGI-1(BAIAP1), Alpha-actinin, Claudin-1, AF-6, VE-cadherin, Connexin 37, Vimentin, Alpha-catenin, Claudin-3, JAM2, Claudin-14


Endothelial cell contacts by junctional mechanisms

Contacts between endothelial cells are important for blood vessel formation. Formation and maintenance of endothelial cell contacts depends on a complex interplay of plasma membrane proteins, cytoskeleton components, and signaling molecules. Some of these molecules are specifically expressed in the specialized cellular 'junctions', which include tight junction, adherens junction, gap junction and desmosomes [1].

Tight junctions seal the endothelial cell layer. They are particularly prolific in endothelia of the blood-brain barrier and in large arteries, in contrast to post-capillary venules [1]. Molecular composition of tight junctions is complex. The only known transmembrane constituents of tight junctions in endothelial cells are Occludin, Claudin 1, Claudin 3, Claudin 5, Claudin 14, Junctional adhesion molecule 1 ( JAM1 ), Junctional adhesion molecule 2 ( JAM2 ) [1]. Several cytoplasmic proteins have been defined as tight junction-associated: Zonula occludens-1 ( ZO-1 ), Zonula occludens-2 ( ZO-2 ), Cingulin, Myeloid/lymphoid or mixed-lineage leukemia; translocated to, 4 ( AF-6 ) [1], [2], Membrane associated guanylate kinase, WW and PDZ domain containing 1 ( MAGI-1(BAIAP1) ). ZO-1 and ZO-2 are found in endothelial cells. ZO-1 and ZO-2 are peripheral membrane scaffolding proteins, specifically associated with the tight junctions [1]. Their function is tetherig transmembrane proteins to the Actin cytoskeletal, also part of tight junctions.

Adherens junctions link an actin bundles between neighboring cells. Adherens junctions are ubiquitously expressed in endothelia of all vascular beds. Adherens junctions in endothelial cells are formed by homofilic binding of Cadherin 5, type 2, a vascular epithelium cadherin ( VE-cadherin ) [1]. Cadherins are cell adhesion molecules anchored by their cytoplasmic tails to a network of intracellular cytoplasmic proteins connected to the actin-based microfilament system. Association with Catenins is nessesary for cadherin-mediated cell adhesion. VE-cadherin interacts via sites within the C-terminal half of its cytoplasmic tail with either Catenin delta 1 ( p120-catenin ) [3] or Catenin (cadherin-associated protein), beta 1 (Beta-catenin) [4], Plakoglobin [5] or Plakophilin 4 [3]. Plakophilin 4 and p120-catenin bind with the same region on the cytoplasmic tail of VE-cadherin. Overexpression of Plakophilin 4 can displace p120-catenin from intercellular junctions [4]. Beta-catenin and Plakoglobin bind Catenin (cadherin-associated protein), alpha 1, 102kDa ( Alpha-catenin ) [6], which, in turn, binds to Actinin, alpha ( Alpha-actinin ) [7], [8], ZO-1 [9] and ZO-2 [10]. Alpha-actinin tethers transmembrane proteins to the Actin cytoskeletal. When junctions stabilize after long periods of confluency, p120-catenin and Beta-catenin dissociate from VE-cadherin and Plakoglobin [11], [1]. MAGI-1(BAIAP1) is mobilized to cell-cell contacts presumably by associating with Beta-catenin. MAGI-1(BAIAP1) is required for VE-cadherin -dependent Rap1 activation [12].

Besides VE-cadherin, Cadherin 2, type 1, N-cadherin (neuronal) ( N-cadherin ) is also found in endothelial cells. In contrast to VE-cadherin, N-cadherin is not concentrated at adherents junctions, but is distributed over the whole cell membrane [13], [1]. N-cadherin also interacts with Plakoglobin, p120-catenin and Beta-catenin [13].

Gap junctions contain hydrophilic membrane channels that allow direct communication between neighboring cells via diffusion of ions, metabolites, and small cell signaling molecules. Gap junctions are clusters of transmembrane chanels formed by connexins made of six connexin monomers [14]. Gap junction proteins, alpha 4, 5 and 1 ( Connexin 37, Connexin 40 and Connexin 43 ) are expressed in endothelial cells [1]. Connexins are probably composed of six identical connexin subunit (homomeric) or more than one connexin isotype (heteromeric). Two identical connexons form homotypic channels, different connexin isotypes form heterotypic channels. [14]. The cytoplasmic domain of Connexin 43 binds ZO-1 [14], [15], ZO-2 [15] and Beta-catenin [16]. These contacts allow close association between gap junctions and cadherin-based adherens junction [14].

Classical desmosomes are not found in endothelial cells, although they express the desmosomal protein Desmoplakin. Desmoplakin is found in desmosome-like structures that have been called 'complexus adhaerentes' [1]. Desmoplakin interacts with Plakoglobin [5], [17] and Vimentin [18].


  1. Vestweber D
    Molecular mechanisms that control endothelial cell contacts. The Journal of pathology 2000 Feb;190(3):281-91
  2. Schneeberger EE, Lynch RD
    The tight junction: a multifunctional complex. American journal of physiology. Cell physiology. 2004 Jun;286(6):C1213-28
  3. Calkins CC, Hoepner BL, Law CM, Novak MR, Setzer SV, Hatzfeld M, Kowalczyk AP
    The Armadillo family protein p0071 is a VE-cadherin- and desmoplakin-binding protein. The Journal of biological chemistry 2003 Jan 17;278(3):1774-83
  4. Tanihara H, Kido M, Obata S, Heimark RL, Davidson M, St John T, Suzuki S
    Characterization of cadherin-4 and cadherin-5 reveals new aspects of cadherins. Journal of cell science 1994 Jun;107 ( Pt 6):1697-704
  5. Kowalczyk AP, Navarro P, Dejana E, Bornslaeger EA, Green KJ, Kopp DS, Borgwardt JE
    VE-cadherin and desmoplakin are assembled into dermal microvascular endothelial intercellular junctions: a pivotal role for plakoglobin in the recruitment of desmoplakin to intercellular junctions. Journal of cell science 1998 Oct;111 ( Pt 20):3045-57
  6. Ozawa M
    Identification of the region of alpha-catenin that plays an essential role in cadherin-mediated cell adhesion. The Journal of biological chemistry 1998 Nov 6;273(45):29524-9
  7. Nieset JE, Redfield AR, Jin F, Knudsen KA, Johnson KR, Wheelock MJ
    Characterization of the interactions of alpha-catenin with alpha-actinin and beta-catenin/plakoglobin. Journal of cell science 1997 Apr;110 ( Pt 8):1013-22
  8. Lilien J, Balsamo J
    The regulation of cadherin-mediated adhesion by tyrosine phosphorylation/dephosphorylation of beta-catenin. Current opinion in cell biology 2005 Oct;17(5):459-65
  9. Itoh M, Nagafuchi A, Moroi S, Tsukita S
    Involvement of ZO-1 in cadherin-based cell adhesion through its direct binding to alpha catenin and actin filaments. The Journal of cell biology 1997 Jul 14;138(1):181-92
  10. Itoh M, Morita K, Tsukita S
    Characterization of ZO-2 as a MAGUK family member associated with tight as well as adherens junctions with a binding affinity to occludin and alpha catenin. The Journal of biological chemistry 1999 Feb 26;274(9):5981-6
  11. Lampugnani MG, Corada M, Caveda L, Breviario F, Ayalon O, Geiger B, Dejana E
    The molecular organization of endothelial cell to cell junctions: differential association of plakoglobin, beta-catenin, and alpha-catenin with vascular endothelial cadherin (VE-cadherin). The Journal of cell biology 1995 Apr;129(1):203-17
  12. Sakurai A, Fukuhara S, Yamagishi A, Sako K, Kamioka Y, Masuda M, Nakaoka Y, Mochizuki N
    MAGI-1 is required for Rap1 activation upon cell-cell contact and for enhancement of vascular endothelial cadherin-mediated cell adhesion. Molecular biology of the cell 2006 Feb;17(2):966-76
  13. Navarro P, Ruco L, Dejana E
    Differential localization of VE- and N-cadherins in human endothelial cells: VE-cadherin competes with N-cadherin for junctional localization. The Journal of cell biology 1998 Mar 23;140(6):1475-84
  14. Wei CJ, Xu X, Lo CW
    Connexins and cell signaling in development and disease. Annual review of cell and developmental biology 2004;20:811-38
  15. Singh D, Solan JL, Taffet SM, Javier R, Lampe PD
    Connexin 43 interacts with zona occludens-1 and -2 proteins in a cell cycle stage-specific manner. The Journal of biological chemistry 2005 Aug 26;280(34):30416-21
  16. Ai Z, Fischer A, Spray DC, Brown AM, Fishman GI
    Wnt-1 regulation of connexin43 in cardiac myocytes. The Journal of clinical investigation 2000 Jan;105(2):161-71
  17. Bornslaeger EA, Godsel LM, Corcoran CM, Park JK, Hatzfeld M, Kowalczyk AP, Green KJ
    Plakophilin 1 interferes with plakoglobin binding to desmoplakin, yet together with plakoglobin promotes clustering of desmosomal plaque complexes at cell-cell borders. Journal of cell science 2001 Feb;114(Pt 4):727-38
  18. Meng JJ, Bornslaeger EA, Green KJ, Steinert PM, Ip W
    Two-hybrid analysis reveals fundamental differences in direct interactions between desmoplakin and cell type-specific intermediate filaments. The Journal of biological chemistry 1997 Aug 22;272(34):21495-503