HECT-Type E3 Ubiquitin Ligases in Cancer

The HECT-type E3 ubiquitin ligases constitute a small subfamily of E3s (28 enzymes in human) that have intrinsic enzymatic activity. Members of the subfamily of HECT-type E3s are frequently deregulated in human cancers. Aberrant expression, mutations, and deregulated activity of the HECT enzymes have been associated with cancer development and chemoresistance. HECT-type E3s contribute to tumorigenesis by regulating the ubiquitination levels of substrates that act as either tumor suppressors or oncogenes. Some HECT E3s behave as pro- or antioncogenic factors depending on the cellular context, substrate selectivity, and binding of adaptor proteins that may facilitate the recruitment of specific targets. Ubiquitination, a post-translational modification that involves a covalent attachment of ubiquitin to a protein substrate, is essential for cellular homeostatic maintenance. At the end of a three-enzyme cascade, E3 ubiquitin ligases (E3s) recruit substrates and promote or directly catalyze ubiquitin transfer to targets. These enzymes largely determine the specificity of the ubiquitination reaction. Genetic alteration, abnormal expression, or dysfunction of E3s account for the occurrence and progression of human cancers. Indeed, excessive degradation of relevant tumor-suppressor molecules and impaired disposal of oncogenic proteins have been linked to tumorigenesis. This review focuses on the emerging roles of HECT-type E3s in tumorigenesis, and emphasizes how perturbations of these enzymes contribute to cancer pathogenesis. Ubiquitination, a post-translational modification that involves a covalent attachment of ubiquitin to a protein substrate, is essential for cellular homeostatic maintenance. At the end of a three-enzyme cascade, E3 ubiquitin ligases (E3s) recruit substrates and promote or directly catalyze ubiquitin transfer to targets. These enzymes largely determine the specificity of the ubiquitination reaction. Genetic alteration, abnormal expression, or dysfunction of E3s account for the occurrence and progression of human cancers. Indeed, excessive degradation of relevant tumor-suppressor molecules and impaired disposal of oncogenic proteins have been linked to tumorigenesis. This review focuses on the emerging roles of HECT-type E3s in tumorigenesis, and emphasizes how perturbations of these enzymes contribute to cancer pathogenesis. refers to irreversible G0/G1 arrest of cell proliferation in response to cellular stress (e.g., oncogenic transformation) which activates a DNA damage response. It represents a barrier to cancer development that is established as the result of the activation of two tumor-suppressor pathways, namely the p53/p21 and the p16/pRB functional axes. a protease that hydrolyzes the isopeptide bond linking ubiquitin to a substrate. The majority of DUBs are Cys proteases that employ their active-site Cys to perform nucleophilic attack on the carbonyl of the isopeptide bond between the target and ubiquitin. The resulting Cys-carbonyl acyl intermediate reacts with a water molecule to release free ubiquitin. transient transdifferentiation of epithelial cells into mesenchymal cells. During EMT epithelial cells reprogram gene expression and, as a result, lose their junctions and apical–basal polarity, and reorganize their cytoskeleton to increase motility and acquire an invasive phenotype. an amide bond that forms between the carboxyl terminus of one amino acid and the amino group of another amino acid, in which at least one of these groups is not on the amino acid α-carbon. the selective degradation of mitochondria by autophagy. Autophagy is a conserved ’self-eating’ process that delivers cytoplasmic material to the lysosome for degradation. It is required for the removal of misfolded or aggregated proteins and damaged organelles. a proteolytic multisubunit complex composed of two 19S regulatory particles and a 20S cylinder-shaped complex, which hydrolyzes unfolded proteins into short peptides. The 19S complex enables the proteasome to drive substrate binding, deubiquitination, unfolding, and translocation to the 20S proteasome proteolytic sites. a zinc-binding structural domain in a protein that contains a series of specifically spaced cysteine and histidine residues placed in a ’cross-brace’ topology to coordinate two zinc ions. These domains are present in many E3s where they mediate the interaction between the E2 and the protein substrate. transfer from a thioester to a thiol group. During the ubiquitination reaction, activated ubiquitin is transferred from the thioester-linked E1–ubiquitin conjugate to the catalytic Cys of a ubiquitin-conjugating enzyme (E2). a ∼40 amino acid modular protein–protein interaction domain that mediates binding to proteins containing Pro-rich motifs (usually including a Tyr residue). The WW domains contain two highly conserved Trp residues and an invariant Pro residue, and WW domains are often present in multiple copies in a polypeptide.