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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

General

nuclear protein Smad ubiquitination regulatory factor

Properties

SIZE: entity length = 748 aa MW = 86 kD COMPARTMENT: cytoplasm cell nucleus MOTIF: C2 domain {1-98} MOTIF: binding site FOR-BINDING-OF: phospholipid Ca+2-binding site WW domain (W/rsp5/WWP domain) {157-190} WW domain (W/rsp5/WWP domain) {251-284} WW domain (W/rsp5/WWP domain) {297-330} HECT domain {414-748} MOTIF: cysteine residue {C716}

References

  1. UniProt :accession Q9HAU4
  2. Izzi L and Attisano L Regulation of the TGFbeta signalling pathway by ubiquitin-mediated degradation Oncogene 23:2071-8, 2004 PMID: 15021894

Databases & Figures

OMIM 605532 UniProt Q9HAU4 PFAM correlations Entrez Gene 64750 Kegg hsa:64750 TGF-beta/BMP signaling