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Gene Review

SMURF2  -  SMAD specific E3 ubiquitin protein ligase 2

Homo sapiens

Synonyms: E3 ubiquitin-protein ligase SMURF2, SMAD ubiquitination regulatory factor 2, SMAD-specific E3 ubiquitin-protein ligase 2, hSMURF2
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Disease relevance of SMURF2


High impact information on SMURF2


Biological context of SMURF2

  • A 2.1 A resolution X-ray crystal structure of the Smurf2 HECT domain reveals that it has a suboptimal E2 binding pocket that could be optimized by mutagenesis to generate a HECT domain that functions independently of Smad7 and potently inhibits TGFbeta signaling [5].
  • Of particular interest, the highly conserved WW domain binding site Trp, which interacts with target PY motifs, is a Phe in the Smurf2 WW3 domain [7].
  • Coexpression of the Smurf2 and Smad7 transgenes exacerbated Smad7-induced abnormalities in hair follicles and sebaceous glands [8].

Associations of SMURF2 with chemical compounds

  • This unusual interaction allows the Smurf2 WW3 domain to recognize a subset of PY motif-containing proteins utilizing an expanded surface to provide specificity [7].

Physical interactions of SMURF2


Regulatory relationships of SMURF2

  • We found that TGF-beta stimulates Smurf2 expression [10].
  • Smurf2 selectively interacts with receptor-regulated Smads and preferentially targets Smad1 for ubiquitination and proteasome-mediated degradation [11].
  • The ability of Smurf2 to promote Smad2 destruction required the HECT catalytic activity of Smurf2 and depended on the proteasome-dependent pathway [12].

Other interactions of SMURF2

  • Moreover, inhibition of the phosphatidil inositol 3 kinase (PI3K)/Akt pathway suppressed TGF-beta-mediated Smurf2 induction [10].
  • Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase [11].
  • Significantly, Smurf2 displayed preference to Smad2 as its target for degradation [12].
  • RNF11 therefore recruits AMSH to Smurf2 for ubiquitination, leading to its degradation by the 26S proteasome [13].
  • In contrast, the lipid raft-caveolar internalization pathway contains the Smad7-Smurf2 bound receptor and is required for rapid receptor turnover [14].

Analytical, diagnostic and therapeutic context of SMURF2


  1. High-level expression of the Smad ubiquitin ligase Smurf2 correlates with poor prognosis in patients with esophageal squamous cell carcinoma. Fukuchi, M., Fukai, Y., Masuda, N., Miyazaki, T., Nakajima, M., Sohda, M., Manda, R., Tsukada, K., Kato, H., Kuwano, H. Cancer Res. (2002) [Pubmed]
  2. The RING-H2 protein RNF11 is overexpressed in breast cancer and is a target of Smurf2 E3 ligase. Subramaniam, V., Li, H., Wong, M., Kitching, R., Attisano, L., Wrana, J., Zubovits, J., Burger, A.M., Seth, A. Br. J. Cancer (2003) [Pubmed]
  3. Abnormal expression of Smurf2 during the process of rat liver fibrosis. Cai, Y., Shen, X.Z., Zhou, C.H., Wang, J.Y. Chinese journal of digestive diseases. (2006) [Pubmed]
  4. Smurf2 up-regulation activates telomere-dependent senescence. Zhang, H., Cohen, S.N. Genes Dev. (2004) [Pubmed]
  5. Regulation of Smurf2 ubiquitin ligase activity by anchoring the E2 to the HECT domain. Ogunjimi, A.A., Briant, D.J., Pece-Barbara, N., Le Roy, C., Di Guglielmo, G.M., Kavsak, P., Rasmussen, R.K., Seet, B.T., Sicheri, F., Wrana, J.L. Mol. Cell (2005) [Pubmed]
  6. TGF-beta induces assembly of a Smad2-Smurf2 ubiquitin ligase complex that targets SnoN for degradation. Bonni, S., Wang, H.R., Causing, C.G., Kavsak, P., Stroschein, S.L., Luo, K., Wrana, J.L. Nat. Cell Biol. (2001) [Pubmed]
  7. An expanded WW domain recognition motif revealed by the interaction between Smad7 and the E3 ubiquitin ligase Smurf2. Chong, P.A., Lin, H., Wrana, J.L., Forman-Kay, J.D. J. Biol. Chem. (2006) [Pubmed]
  8. Smad7-induced beta-catenin degradation alters epidermal appendage development. Han, G., Li, A.G., Liang, Y.Y., Owens, P., He, W., Lu, S., Yoshimatsu, Y., Wang, D., Ten Dijke, P., Lin, X., Wang, X.J. Dev. Cell (2006) [Pubmed]
  9. Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation. Kavsak, P., Rasmussen, R.K., Causing, C.G., Bonni, S., Zhu, H., Thomsen, G.H., Wrana, J.L. Mol. Cell (2000) [Pubmed]
  10. Transcriptional induction of Smurf2 ubiquitin ligase by TGF-beta. Ohashi, N., Yamamoto, T., Uchida, C., Togawa, A., Fukasawa, H., Fujigaki, Y., Suzuki, S., Kitagawa, K., Hattori, T., Oda, T., Hayashi, H., Hishida, A., Kitagawa, M. FEBS Lett. (2005) [Pubmed]
  11. Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase. Zhang, Y., Chang, C., Gehling, D.J., Hemmati-Brivanlou, A., Derynck, R. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  12. Smurf2 is a ubiquitin E3 ligase mediating proteasome-dependent degradation of Smad2 in transforming growth factor-beta signaling. Lin, X., Liang, M., Feng, X.H. J. Biol. Chem. (2000) [Pubmed]
  13. An RNF11: Smurf2 complex mediates ubiquitination of the AMSH protein. Li, H., Seth, A. Oncogene (2004) [Pubmed]
  14. Distinct endocytic pathways regulate TGF-beta receptor signalling and turnover. Di Guglielmo, G.M., Le Roy, C., Goodfellow, A.F., Wrana, J.L. Nat. Cell Biol. (2003) [Pubmed]
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