E3 ubiquitin-protein ligase SMURF2; hSMURF2; SMAD ubiquitination regulatory factor 2; SMAD-specific E3 ubiquitin-protein ligase 2 (SMURF2)

Function

• E3 ubiquitin-protein ligase
• accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester & then directly transfers the ubiquitin to targeted substrates
• interacts with SMAD1 & SMAD7 in order to trigger their ubiquitination & proteasome-dependent degradation
• in addition, interaction with SMAD7 activates autocatalytic degradation, which is prevented by interaction with SCYE1
• forms a stable complex with the TGF-beta receptor-mediated phosphorylated SMAD2 & SMAD3
  • in this way, SMAD2 may recruit substrates, such as SNON, for ubiquitin-mediated degradation
• enhances inhibitory activity of SMAD7 & reduces the transcriptional activity of SMAD2.
• coexpression of SMURF2 with SMAD1 results in a large decrease in steady-state level of SMAD1 & a smaller decrease of SMAD2
• activated by NDFIP1- & NDFIP2-binding
• protein modification; protein ubiquitination
• auto-ubiquitinated & ubiquitinated in the presence of RNF11 & UBE2D1
• ubiquitinated by the SCF complex (FBXL15), leading to its degradation by the proteasome
• interacts (via WW domains) with SMAD1
• interacts (via WW domains) with SMAD2 (via PY-motif)
• interacts (via WW domains) with SMAD3 (via PY-motif)
• interacts with SMAD6
• interacts with SMAD7 (via PY-motif) & TGFBR1
  • SMAD7 recruits SMURF2 to the TGF-beta receptor & regulates its degradation
• does not interact with SMAD4; SMAD4 lacks a PY-motif
• interacts with AIMP1
• interacts with STAMBP & RNF11
• interacts with NDFIP1 & NDFIP2 (probable)
  • this interaction activates the E3 ubiquitin-protein ligase

Structure

• the second & third WW domains are responsible for interaction with the PY-motif of R-SMAD (SMAD1, SMAD2 & SMAD3)
• the C2 domain is involved in autoinhibition of the catalytic activity by interacting with the HECT domain
• contains 1 C2 domain
• contains 1 HECT domain (E6AP-type E3 ubiquitin-protein ligase)
• contains 3 WW domains

Compartment

• nucleus, cytoplasm
• cell membrane
• cytoplasmic in the presence of SMAD7
• colocalizes with CAV1, SMAD7 & TGF-beta receptor in membrane rafts

Expression

widely expressed

More general terms

• Smad ubiquitination regulatory factor
• nuclear protein

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=64750
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:64750
• OMIM: https://mirror.omim.org/entry/605532
• UniProt: http://www.uniprot.org/uniprot/Q9HAU4.html