Smurf E3 ubiquitin ligases at the cross roads of oncogenesis and tumor suppression

Abstract

Smad ubiquitin regulatory factors (Smurfs) belong to the HECT- family of E3 ubiquitin ligases and comprise mainly of two members, Smurf1 and Smurf2. Initially, Smurfs have been implicated in determining the competence of cells to respond to TGF-β/BMP signaling pathway. Nevertheless, the intrinsic catalytic activity has extended the repertoire of Smurf substrates beyond the TGF-β/BMP super family expanding its realm further to epigenetic modifications of histones governing the chromatin landscape. Through regulation of a large number of proteins in multiple cellular compartments, Smurfs regulate diverse cellular processes, including cell-cycle progression, cell proliferation, differentiation, DNA damage response, maintenance of genomic stability, and metastasis. As the genomic ablation of Smurfs leads to global changes in histone modifications and predisposition to a wide spectrum of tumors, Smurfs are also considered to have a novel tumor suppressor function. This review focuses on regulation network and biological functions of Smurfs in connection with its role in cancer progression. By providing a portrait of their protein targets, we intend to link the substrate specificity of Smurfs with their contribution to tumorigenesis. Since the regulation and biological functions of Smurfs are quite complex, understanding the oncogenic potential of these E3 ubiquitin ligases may facilitate the development of mechanism-based drugs in cancer treatment.

Introduction

Protein ubiquitination, a post translational modification, mediated by the ubiquitin–proteasome system (UPS) plays an essential regulatory role in critical cellular processes including cell cycle, cell proliferation, differentiation, angiogenesis, stem cell quiescence, DNA damage repair, and apoptosis. Clearly, a process that is so critical for cellular homeostasis is itself tightly regulated by multiple enzymatic steps catalyzed by ubiquitin-activating enzyme E1, ubiquitin-conjugating enzyme E2, and ubiquitin ligase E3, and many accessory proteins that provide specificity to the system. Specifically, E3 ubiquitin ligases (E3s) play an indispensable role in this cascade by recruiting ubiquitin-loaded E2s, recognizing specific substrates, and facilitating or directly catalyzing ubiquitin transfer to the respective molecular targets. The relevance of the E3s in several biological processes is emphasized in vivo by the observation that their genetic alteration, abnormal expression, or dysfunction is often accompanied by the occurrence of pathological disorders, including cancer. Recently various HECT E3 ubiquitin ligases have emerged as crucial regulators of cancer development. Indeed, in view of their substrate specificity, the E3s represent potentially attractive targets for anticancer treatment [1], [2], [3].

Smurfs are popularly known as little blue comic creatures and are versatile. Similarly in molecular biology the two Smurfs, Smurf1 (Smad ubiquitination-related factor 1) and Smurf2 constitute the Smurf village which are closely related C2-WW-HECT-domain E3 ubiquitin ligases that play important roles in determining the competence of cells to respond to TGF- β/BMP signaling pathway [4], [5]. However, the pleiotropic effect of Smurfs has expanded the repertoire of its substrates beyond the TGF-β/BMP super family ranging from planar cell polarity during embryonic development to cell proliferation, migration, differentiation and senescence [6], [7], [8], [9], [10], [11]. Notably, aberrant expression of Smurfs occurs in several types of cancers, including breast, esophageal, pancreatic and renal cell carcinomas [12], [13], [14], [15], [16]. In contrast, Smurfs are found to induce senescence [10] and recent mouse model studies by Blank et al. [17] showed that Smurf2 is a bona fide tumor suppressor, as the Smurf2-deficient mice are prone to a variety of cancers, including lymphoma, hepatocellular, lung and mammary carcinoma.

Since Smurfs are considered to play a contradictory role as tumor promoter and suppressor, understanding the biological functions of Smurfs and its associated regulatory networks would be crucial for providing insights into the mechanisms of Smurf-mediated cancer progression and also in developing therapeutic strategies that target the Smurf pathway in human cancers. In this review, we focus on the major functions and regulatory network of Smurfs, as well as their role in human cancer.