Pathway Map Details
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 .
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 . 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 ) . 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 ) , , 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 . 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 ) . 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 )  or Catenin (cadherin-associated protein), beta 1 (Beta-catenin) , Plakoglobin  or Plakophilin 4 . 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 . Beta-catenin and Plakoglobin bind Catenin (cadherin-associated protein), alpha 1, 102kDa ( Alpha-catenin ) , which, in turn, binds to Actinin, alpha ( Alpha-actinin ) , , ZO-1  and ZO-2 . 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 , . 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 .
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 , . N-cadherin also interacts with Plakoglobin, p120-catenin and Beta-catenin .
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 . Gap junction proteins, alpha 4, 5 and 1 ( Connexin 37, Connexin 40 and Connexin 43 ) are expressed in endothelial cells . 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. . The cytoplasmic domain of Connexin 43 binds ZO-1 , , ZO-2  and Beta-catenin . These contacts allow close association between gap junctions and cadherin-based adherens junction .
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' . Desmoplakin interacts with Plakoglobin ,  and Vimentin .
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