Smurf2, short for Smad ubiquitin regulatory factor 2, is an E3 ubiquitin ligase. It is an essential negative regulator of TGF-β signaling, ubiquitinating TGF-β receptors (TβRs) and Smad proteins, which leads to their proteasomal degradation. This regulation is crucial for maintaining normal cellular functions and tissue homeostasis. Dysfunction of Smurf2 can trigger abnormal TGF-β signaling in pathological states [3].

Loss of SMURF2 expression enhances RACK1 stability and promotes ovarian cancer progression. SMURF2 acts as a bona fide E3 ligase of RACK1, adding ubiquitin chains to RACK1, resulting in its polyubiquitination and instability. In human ovarian cancer, low SMURF2 expression leads to increased RACK1 stability, promoting tumorigenesis [1]. In non-small cell lung cancer, SMURF2 expression is reduced in tumor tissues. Overexpression of SMURF2 inhibits lung cancer cell progression by promoting the poly-ubiquitination and degradation of ID2, which dissociates endogenous transcription factor E2A and induces G1/S arrest [2]. SMURF2 phosphorylation at Thr249 is important for maintaining glioma stem cell (GSC) phenotypes. Silencing SMURF2 or introducing a phosphorylation-defective mutant increases GSC self-renewal and tumorigenicity by increasing TGF-β receptor protein stability [4].

In summary, Smurf2 plays a significant role in multiple biological processes and disease conditions, especially in cancer. Loss-of-function studies, such as those in ovarian cancer, non-small cell lung cancer, and glioma, have revealed its tumor-suppressive functions. These findings suggest that Smurf2 could be a potential therapeutic target for treating related cancers.