THE CADHERIN SUPERFAMILY: BIOLOGICAL SIGNIFICANCE AND NEUROLOGICAL DIVERSITY
Zaharieva I*
*Corresponding Author: Dr. Irina Zaharieva, Department of Medical Genetics, Medical University Sofia, 2 Zdrave str, 1431 Sofia, Bulgaria; Tel./Fax: +359-2-952-03-57; E-mail: irinazaharieva@yahoo.co.uk
page: 19

CLASSICAL CADHERINS

Classical cadherins are single-pass transmembrane proteins that are primarily located within adherence junc­tions. They contain five EC domains and through them mediate Ca2+-dependant cell-cell adhesion. They partici­pate in cell sorting and carry out specific functions, de­pending on the specific interaction of the extracellular regions. Through their intracellular regions they can inter­act with β-catenin or plakoglobin (PG), and consequently to α-catenin and the actin filament network.

      Classical cadherins form lateral homodimers and inter­act with the homodimers of the neighboring cell in a head-to-head manner. The cadherin repeat 1 plays a crucial role in this interaction. Critical to the formation of the stable interactions are the His-Ala-Val sequence and the residues surrounding that repeat. The alanine residue is highly con­servative among the cadherins and its role is in maintain­ing the structure of the cadherin domain rather than in adhesive contacts [3].

      The epidermal and neuronal cadherin (E-cadherin, N-cadherin) are subject to profound research. E-cadherin is expressed primarily in epithelial cells, is encoded by the CDH1 gene, and is involved in development, tissue integ­rity, cell migration, morphology and polarity. E-cadherin is also a tumor suppressor whose expression is frequently reduced or silenced in many cancers. E-cadherin can par­ticipate in signal transduction although this function has not been clearly proven. Epidermal growth factor receptor (EGFR) and c-Met, which are receptor protein tyrosine kinases, co-localize with E-cadherin to baso-lateral areas of polarized epithelial cells and form multi-component complexes, although the functional consequences of these associations have not been clearly identified [4].

      N-cadherin is expressed thoroughly in the nervous system, and is important for the development and func­tional organization of the adult neural tissue. In the early stages of development, it is implicated in axon guidance and neurite outgrowth. Later in development, N-cadherin is localized in the synapses and functions not only as an adhesive molecule but also participates in synaptic func­tion and plasticity [5-9].

      Another member of classical cadherins is vascular endothelial cadherin (VE-cadherin), which plays an impor­tant role in vasculogenesis and vascular remodeling. Like E-cadherin, it is expressed in epithelial cells but whereas E-cadherin is distributed randomly on the surface, VE-cadherin is located to adherence junctions. Key feature of that protein is its ability to bind to several cytoplasmic binding partners: it binds to β-catenin which in turn binds to α-catenin and the actin filament network. Other possible cytoplasmic partners are p120ctn and PG. Placoglobin fur­ther interacts with desmoplakin (DP) and thus allows a link to the intermediate filament network. Thereby, VE-cadherin enables endothelial cells to form two types of adhesive complexes, with the actin or with the intermedi­ate filament network.

 




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