Smurfs in Protein Homeostasis, Signaling, and Cancer

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.

The E3 ubiquitin ligase Smurf2 regulates PARP1 stability to alleviate oxidative stress‐induced injury in human umbilical vein endothelial cells

“…Smurf2 belongs to the HECT family of E3 ubiquitinated ligases and was originally thought to play a crucial role in embryogenesis, adult tissue homeostasis and the pathogenesis of various human diseases . As E3 ubiquitination ligase Smurf2 has many binding substrates, such as TGF‐β receptor to regulate TGF‐β pathway, binding with PTEN to sequential recruitment of activated Akt and NF‐κB‐inducing kinase (NIK) and interacting with DNA topoisomerase IIα (Topo IIα) ensure genomic integrity and unaltered chromosome inheritance . However, there are few reports of the involvement of Smurf2 in cardiovascular diseases.…”

“…Smurf2, a C2‐WW‐HECT‐domain E3 ubiquitin ligase belonging to the NEDD4 subfamily of HECT‐type E3 ligases, is similar to other NEDD4 family members (9 in total) . Smurf2 participates in many cellular physiological processes through the ubiquitin‐proteasome pathway.…”

Emerging roles of HECT‐type E3 ubiquitin ligases in autophagy regulation

“…Emerging evidence has highlighted that HECT E3s play relevant roles in cancer development and progression by regulating the degradation or the activity of both oncogenes and tumor suppressors. As a consequence, abnormal expression, dysfunction, and mutations of the HECT enzymes have been associated with cancer development and chemoresistance (Kao et al, 2018;Koganti et al, 2018;Lee et al, 2019;Melino et al, 2008;Sanarico et al, 2018).…”

The conserved ancestral signaling pathway from cilium to nucleus

“…In the case of Hh signaling, Ptch1 has been shown to exit the cilium through endocytosis into caveolin-containing vesicles (Yue et al, 2014); this is dependent on the specific ubiquitin ligases Smurf1 and Smurf2, SMAD-related signaling scaffold molecules, which help to deliver Ptch1 to lysosomes for degradation and could themselves translocate into the nucleus (Koganti et al, 2018).…”