Abstract
In order to metastasize, cancer cells must first detach from the primary tumor, migrate, invade through tissues, and attach to a second site. Hakai was discovered as an E3 ubiquitin-ligase that mediates the posttranslational downregulation of E-cadherin, a major component of adherens junctions in epithelial cells that is characterized as a potent tumor suppressor and is modulated during various processes including epithelial–mesenchymal transition. Recent data have provided evidences for novel biological functional role of Hakai during tumor progression and other diseases. Here, we will review the knowledge that has been accumulated since Hakai discovery 10 years ago and its implication in human cancer disease. We will highlight the different signaling pathways leading to the influence on Hakai and suggest its potential usefulness as therapeutic target for cancer.
Highlights
Most of the human common tumors are carcinomas; which arise from epithelial cells
The cytoplasmic domain of the E-cadherin contains two sequences, cadherin homology 2 (CH2) and cadherin homology 3 (CH3) domains, conserved between classical cadherins; respectively [35, 36]. p120 and β-catenin can interact with these two domains, respectively; its interaction does not depend on the activation of trp-Met
These results suggested that Hakai coexist with E-cadherin in an intracellular vesicle compartment that still has not been identified
Summary
In polarized epithelia of vertebrates, adhesion between epithelial cells is mediated by distinct junctional complexes named tight junctions, at the apical site, adherens junctions (AJ) at the subapical site, and desmosomes, at basolateral site [10]; these three types of junctions are linked to the cytoskeletal filaments. The extracellular domain is divided into five repetitive subdomains, called cadherin repeats, and every subdomain contain calcium-binding sequences [20]. The cytoplasmic domain is highly conserved among classical cadherins and interacts with cytosolic proteins called catenins [21,22,23]. Cadherin-based cell–cell contacts are not static but are often dynamically modulated during various physiological and pathological processes including mitosis, epithelial–mesenchymal transition during tumor progression and embryonic development. In all these processes, cadherin has been reported to be downregulated
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