Oligoventin

Members of the HECT family of E3 ubiquitin-protein ligases are characterized by a C-terminal HECT domain that catalyzes the covalent attachment of ubiquitin to substrate proteins and by N-terminal extensions of variable length and domain architecture that determine the substrate spectrum of a respective HECT E3. Since their discovery in 1995, it has become clear that deregulation of distinct HECT E3s plays an eminent role in human disease or disease-related processes including cancer, cardiovascular and neurological disorders, viral infections, and immune response. Thus, a detailed understanding of the structure-function aspects of HECT E3s as well as the identification and characterization of the substrates and regulators of HECT E3s is critical in developing new approaches in the treatment of respective diseases. In this review, we summarize what is currently known about mammalian HECT E3s, with a focus on their biological functions and roles in pathophysiology.This article is part of a Special Issue entitled: Ubiquitin-Proteasome System. Guest Editors: Thomas Sommer and Dieter H. Wolf.

Background: HECT ubiquitin ligases (HECT E3s) are key components of the eukaryotic ubiquitin-proteasome system and are involved in the genesis of several human diseases. In this study, I analyze the patterns of diversification of HECT E3s since animals emerged in order to provide the right framework to understand the functional data available for proteins of this family. Results: I show that the current classification of HECT E3s into three groups (NEDD4-like E3s, HERCs and single-HECT E3s) is fundamentally incorrect. First, the existence of a "Single-HECT E3s" group is not supported by phylogenetic analyses. Second, the HERC proteins must be divided into two subfamilies (Large HERCs, Small HERCs) that are evolutionarily very distant, their structural similarity being due to convergence and not to a common origin. Sequence and structural analyses show that animal HECT E3s can be naturally classified into 16 subfamilies. Almost all of them appeared either before animals originated or in early animal evolution. More recently, multiple gene losses have occurred independently in some lineages (nematodes, insects, urochordates), the same groups that have also lost genes of another type of E3s (RBR family). Interestingly, the emergence of some animal HECT E3s precedes the origin of key cellular systems that they regulate (TGF-beta and EGF signal transduction pathways; p53 family of transcription factors) and it can be deduced that distantly related HECT proteins have been independently co-opted to perform similar roles. This may contribute to explain why distantly related HECT E3s are involved in the genesis of multiple types of cancer. Conclusions: The complex evolutionary history of HECT ubiquitin ligases in animals has been deciphered. The most appropriate model animals to study them and new theoretical and experimental lines of research are suggested by these results.

Ubiquitination-mediated proteolysis or regulation of proteins, ultimately executed by E3 ubiquitin ligases, control a wide array of cellular processes, including transcription, cell cycle, autophagy and apoptotic cell death. HECT-type E3 ubiquitin ligases can be distinguished from other subfamilies of E3 ubiquitin ligases because they have a C-terminal HECT domain that directly catalyzes the covalent attachment of ubiquitin to their substrate proteins. Deregulation of HECT-type E3-mediated ubiquitination plays a prominent role in cancer development and chemoresistance. Several members of this subfamily are indeed frequently deregulated in human cancers as a result of genetic mutations and altered expression or activity. HECT-type E3s contribute to tumorigenesis by regulating the ubiquitination rate of substrates that function as either tumour suppressors or oncogenes. While the pathological roles of the HECT family members in solid tumors are quite well established, their contribution to the pathogenesis of hematological malignancies has only recently emerged. This review aims to provide a comprehensive overview of the involvement of the HECT-type E3s in leukemogenesis.