The reference OMIM entry for this protein is 605568

Smad-specific e3 ubiquitin protein ligase 1; smurf1
Smad ubiquitination regulatory factor 1

CLONING

Using a yeast 2-hybrid screen with frog Smad1 (601595) as bait, Zhu et al. (1999) identified cDNAs encoding frog and human SMURF1. Frog and human SMURF1 contain 731 amino acids, share 91% identity, are most closely related to yeast Pub1, and have significant homology to the Hect subclass of E3 ubiquitin ligases.

GENE FUNCTION

Zhu et al. (1999) found that expression of SMURF1 caused a dose-dependent decrease in expression of SMAD1 and SMAD5 (603110), which function in bone morphogenetic protein (BMP; see 603248) signaling, but not in expression of SMAD2 (601366) or SMAD3 (603109), which function in TGFB (190180) signaling. Pulse-chase analysis demonstrated that degradation of SMAD proteins occurs by ubiquitination of the SMAD Hect domain and transport to the proteasome. Mutational analysis indicated that the WW motif of SMURF1 associates with SMAD1 and SMAD5 through their PY motifs. In frog eggs, Smurf1 mRNA was localized to the animal pole; ectopic Smurf1 in frog embryos inhibited the transmission of BMP signals, affecting pattern formation. Wang et al. (2003) found that Smurf1, a HECT domain E3 ubiquitin ligase, regulated cell polarity and protrusive activity and was required to maintain the transformed morphology and motility of a tumor cell. Atypical protein kinase C-zeta (PKC2; 176982), an effector of the Cdc42 (116952)/Rac1 (602048)-PAR6 (607484) polarity complex, recruited Smurf1 to cellular protrusions, where it controlled the local level of RhoA (165390). Smurf1 thus links the polarity complex to degradation of RhoA in lamellipodia and filopodia to prevent RhoA signaling during dynamic membrane movements. Using RNA interference, Crose et al. (2009) showed that knockdown of Ccm2 (607929) in mouse brain endothelial cells led to increased monolayer permeability, decreased tubule formation, and reduced cell migration following wounding. These effects were associated with elevated levels of RhoA. Coimmunoprecipitation analysis revealed that Ccm2 directly bound Smurf1. Domain analysis revealed that the PTB domain of Ccm2 directly bound the HECT domain of Smurf1, and the interaction targeted Smurf1 to Ccm2 complexes localized primarily at the cell periphery. Coexpression of Ccm2 and Smurf1 led to cell rounding, likely due to loss of RhoA. Crose et al. (2009) concluded that CCM2 contributes to endothelial cell integrity by regulating SMURF1-directed RHOA degradation Orvedahl et al. (2011) performed a high-content, image-based, genomewide small interfering RNA screen to detect genes required for the colocalization of Sindbis virus capsid protein with autophagolysosomes. They identified 141 candidate genes required for viral autophagy, which were enriched for cellular pathways related to mRNA processing, interferon signaling, vesicle trafficking, cytoskeletal motor function, and metabolism. Ninety-six of these genes were also required for Parkin (602544)-mediated mitophagy, indicating that common molecular determinants may be involved in autophagic targeting of viral nucleocapsids and autophagic targeting of damaged mitochondria. Murine embryonic fibroblasts lacking one of these gene products, the C2 domain-containing protein SMURF1, are deficient in the autophagosomal targeting of Sindbis and herpes simplex viruses and in the clearance of damaged mitochondria. Moreover, SMURF1-deficient mice accumulated damaged mitochondria in the heart, brain, and liver. Thus, Orvedahl et al. (2011) concluded that their stu ... More on the omim web site

Subscribe to this protein entry history

June 30, 2020: Protein entry updated
Automatic update: OMIM entry 605568 was added.

Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).