SMURF2

SMURF2 (SMAD ubiquitination regulatory factor 2) is an E3 ubiquitin ligase of the HECT family that regulates signaling pathways linked to the TGF-β superfamily. The human SMURF2 gene encodes a protein with an N-terminal C2 lipid-binding domain, two WW domains, and a C-terminal HECT catalytic domain. The WW domains recognize PPxY motifs in substrates, enabling interaction with components of the TGF-β/BMP pathways, including SMAD transcription factors.

SMURF2 modulates signaling primarily by ubiquitinating receptor-regulated SMADs (SMAD2/3 and SMAD1/5/8) and, in some contexts, the type I receptors (such as ALK5), promoting proteasomal degradation or receptor downregulation. This action generally attenuates TGF-β and BMP signaling, influencing processes such as cell proliferation, differentiation, epithelial-mesenchymal transition, and developmental patterning.

In cancer biology, SMURF2 can act as a context-dependent regulator, contributing to tumor suppression by limiting pro-oncogenic TGF-β signaling, or, in other contexts, promoting tumor progression through alterations of SMAD signaling and noncanonical pathways.

Beyond SMADs, SMURF2 participates in broader cellular processes including regulation of cell polarity, cytoskeletal organization, and bone remodeling through interactions with BMP signaling. Its activity is controlled by post-translational modifications and interacting proteins that influence substrate selection.

Dysregulation of SMURF2 has been associated with fibrosis and cancer, making it a focus of research into therapeutic strategies to modulate TGF-β/BMP signaling.