Abstract
Protein ubiquitination is an evolutionary conserved highly-orchestrated enzymatic cascade essential for normal cellular functions and homeostasis maintenance. This pathway relies on a defined set of cellular enzymes, among them, substrate-specific E3 ubiquitin ligases (E3s). These ligases are the most critical players, as they define the spatiotemporal nature of ubiquitination and confer specificity to this cascade. Smurf1 and Smurf2 (Smurfs) are the C2-WW-HECT-domain E3 ubiquitin ligases, which recently emerged as important determinants of pivotal cellular processes. These processes include cell proliferation and differentiation, chromatin organization and dynamics, DNA damage response and genomic integrity maintenance, gene expression, cell stemness, migration, and invasion. All these processes are intimately connected and profoundly altered in cancer. Initially, Smurf proteins were identified as negative regulators of the bone morphogenetic protein (BMP) and the transforming growth factor beta (TGF-β) signaling pathways. However, recent studies have extended the scope of Smurfs' biological functions beyond the BMP/TGF-β signaling regulation. Here, we provide a critical literature overview and updates on the regulatory roles of Smurfs in molecular and cell biology, with an emphasis on cancer. We also highlight the studies demonstrating the impact of Smurf proteins on tumor cell sensitivity to anticancer therapies. Further in-depth analyses of Smurfs' biological functions and influences on molecular pathways could provide novel therapeutic targets and paradigms for cancer diagnosis and treatment.
Highlights
Protein ubiquitination is a major posttranslational modification that controls a wide spectrum of biological functions, and is critical in maintaining cellular homeostasis under physiological conditions and in diseases.Ubiquitination is a multi-step enzymatic process which is mediated by the concerted action of three main types of proteins: (i) ubiquitin-activating enzymes (E1s), which bind, adenylate and activate cognate ubiquitin molecules using the energy of ATP hydrolysis; (ii) ubiquitin-conjugating enzymes (E2s), which accept ubiquitin from E1 in the form of a thioester bond to their active-site cysteine; and (iii) ubiquitin protein ligases (E3s) that recruit ubiquitin-charged E2 enzymes and mediate specific transfers of ubiquitin to protein substrates.It is estimated that the human genome encodes for more than 630 E3 ubiquitin ligases (E3s), ∼40 E2s, and only two E1s
The vast majority of tumors in p53-null mice are hematological malignancies, which develop within a few months after the animal’s birth [28, 29]. These findings suggest that the Smurf2-ablated animals are highly relevant to human carcinogenesis model, and could be advantageous when studying cancer-related processes at the whole organism level
We further demonstrated that these Smurf2 activities were associated with and at least in part relied on its ability to ubiquitinate and degrade Ring Finger Protein 20 (RNF20) (Figure 2), a really interesting new gene (RING) type E3 ubiquitin ligase responsible for monoubiquitination of histone Histone H2B (H2B)
Summary
Protein ubiquitination is a major posttranslational modification that controls a wide spectrum of biological functions, and is critical in maintaining cellular homeostasis under physiological conditions and in diseases. E3s tightly control protein stability, localization, and function, and thereby regulate a plethora of biological processes. This has instigated intensive investigations of these enzymes as disease biomarkers and drug targets in a variety of human disorders, in cancer [1,2,3]. Smurfs share a high sequence homology (>70% amino acid sequence identity) and have similar structural characteristics. Despite these high similarities and some redundancy in their substrate repertoire, these proteins exhibit distinct and in some respects opposite biological functions. We highlight studies implicating Smurfs in cellular responses to anticancer therapies
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