SMURF1

SMURF1, or SMAD ubiquitination regulatory factor 1, is an E3 ubiquitin-protein ligase of the HECT family that regulates signaling by promoting ubiquitination and proteasomal degradation of target proteins. In humans, SMURF1 is encoded by the SMURF1 gene and is expressed in multiple tissues, where it participates in modulating signaling pathways and cellular behavior.

Protein structure: SMURF1 contains an N-terminal C2 domain that supports membrane association, two WW domains that recognize proline-rich motifs, and a C-terminal HECT catalytic domain responsible for ubiquitin transfer. This domain organization enables substrate recognition and ubiquitination.

Function and mechanism: SMURF1 negatively regulates TGF-β and BMP signaling by ubiquitinating receptor-regulated SMADs (SMAD2/3 and SMAD1/5/8) and, in some contexts, type I receptors, leading to degradation or functional inhibition of components of these pathways. This activity provides negative feedback to TGF-β/BMP signaling. SMURF1 also targets cytoskeletal regulators such as RhoA, influencing cell shape, migration, and cytoskeletal organization. Through these actions, SMURF1 participates in developmental processes, tissue remodeling, and epithelial-to-mesenchymal transitions.

Regulation: Its activity is modulated by interactions with inhibitory SMADs (for example SMAD7), phosphorylation, and subcellular localization, enabling context-dependent effects on signaling.

Clinical relevance: Altered SMURF1 activity has been linked to pathological conditions including cancer and fibrotic diseases, making it a focus of basic and translational research as a potential therapeutic target.

Species: The SMURF1 gene and protein are conserved in vertebrates and have been studied in human cells and model organisms.