Abstract
HERC proteins are ubiquitin E3 ligases of the HECT family. The HERC subfamily is composed of six members classified by size into large (HERC1 and HERC2) and small (HERC3–HERC6). HERC family ubiquitin ligases regulate important cellular processes, such as neurodevelopment, DNA damage response, cell proliferation, cell migration, and immune responses. Accumulating evidence also shows that this family plays critical roles in cancer. In this review, we provide an integrated view of the role of these ligases in cancer, highlighting their bivalent functions as either oncogenes or tumor suppressors, depending on the tumor type. We include a discussion of both the molecular mechanisms involved and the potential therapeutic strategies.
Highlights
Ubiquitin E3 ligases take part in protein ubiquitylation
USP16 triggers the ubiquitylation signal termination once the damage is repaired. These findings suggest that HERC2 has a central role in regulating and fine-tuning the DNA damage response pathway (Figure 2B) [59]
mitogen-activated protein kinase (MAPK) are organized in three-tiered cascades regulated by phosphorylation: MAPKK kinases (MAPKKKs) are serine/threonine-protein kinases that phosphorylate and activate MAPKKs, which in turn phosphorylate the MAPKs that mediate the cellular response by phosphorylating effector proteins
Summary
Ubiquitin E3 ligases take part in protein ubiquitylation. All HECT ligases have a catalytic domain in their carboxyl terminus that contains a conserved cysteine residue that is involved in forming a transiently thioester bond to ubiquitin before transferring it to the lysine residue of the substrate protein (Figure 1) [1]. HERC1 and HERC2 are the largest HECT ligases, having molecular weights exceeding 500 kDa, and constitute the large HERC protein subfamily [3]. Despite the structural similarity between large and small HERC proteins (Figure 1), they are evolutionarily very distant. They are the result of convergence phenomena rather than being phylogenetic paralogs [3,4,5].
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