Disease relevance of SMURF1

• In this study, we show that Smurf1 enhances neurite outgrowth in Neuro2a neuroblastoma cells [1].

High impact information on SMURF1

• Ubiquitin ligase Smurf1 controls osteoblast activity and bone homeostasis by targeting MEKK2 for degradation [2].
• Specifically, acetylation of Smad7 protects it against ubiquitination and degradation mediated by the ubiquitin ligase Smurf1 [3].
• Impaired Smad7-Smurf-mediated negative regulation of TGF-beta signaling in scleroderma fibroblasts [4].
• Our results suggest that Smurf1 is a pivotal regulator of tumor cell movement through its regulation of RhoA signaling [5].
• In 3D invasion assays, and in in vivo tumor cell migration, the inhibition of Smurf1 induces a mesenchymal-amoeboid-like transition that is associated with a more invasive phenotype [5].

Biological context of SMURF1

• Here we identified a functional nuclear export signal (NES) in a C-terminal region of Smurf1 [6].
• Finally, the Smurf1 NES mutant reduced inhibition by Smad7 of the transcriptional activation induced by TGF-beta [6].
• In previous studies we discovered that E3 ubiquitin ligase Smad ubiquitin regulatory factor 1 (Smurf1) induces Runx2 degradation in a ubiquitin-proteasome-dependent manner, and Smurf1 plays an important role in osteoblast function and bone formation [7].
• We determined that LMP-1, a LIM domain protein capable of inducing de novo bone formation, interacts with Smurf1 (Smad ubiquitin regulatory factor 1) and prevents ubiquitination of Smads [8].
• Previous work has demonstrated in non-neuronal cell types that Smurf1, an E3 ubiquitin ligase, regulates cell polarity and protrusive activity via PKCzeta-dependent recruitment to cellular protrusion sites, and subsequent ubiquitination and proteasomal degradation of RhoA [1].

Anatomical context of SMURF1

• We show here that Smurf1 targets Smad7 to the plasma membrane through its N-terminal conserved 2 (C2) domain [9].
• We demonstrate that ectopic expression of Smurf1 in Vero cells, deficient for RhoA ubiquitylation, restores ubiquitylation of the activated forms of RhoA [10].
• We conclude here that Smurf1 ubiquitylates activated RhoA and that, in contrast to human primary cell types, some cancer cell lines have a lower ubiquitylation capacity of specific Rho proteins [10].
• Smurf1, in turn, targets the guanosine triphosphatase RhoA for degradation, thereby leading to a loss of tight junctions [11].

Associations of SMURF1 with chemical compounds

• A green fluorescence protein fusion protein containing the C-terminal NES motif of Smurf1, located in the cytoplasm, accumulated in the nucleus following treatment with leptomycin B [6].
• The p300-dependent acetylation of three lysine residues protects RUNX3 from ubiquitin ligase Smurf-mediated degradation [12].
• Interestingly, Smurf1 overexpression in Neuro2a cells dramatically reduces RhoA protein levels during dibutyric cyclic AMP, but not retinoic acid induced neurite outgrowth [1].

Physical interactions of SMURF1

• Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation [13].
• Smurf1 also interacts directly with either nucleotide-free or GDP-bound RhoA in vitro; however, loading with GTPgammaS inhibits the interaction [14].

Regulatory relationships of SMURF1

• This Smad7 inhibition is enhanced by co-expression of Smurf1 [15].
• In the present studies we investigated the molecular mechanism of Smurf1-induced Runx2 degradation [7].
• Smurf2 interacted with Smurf1 and induced its ubiquitination and degradation, whereas Smurf1 failed to induce degradation of Smurf2 [16].

Other interactions of SMURF1

• However, the mechanism of nuclear export of Smad7 by Smurf1 has not been elucidated [6].
• Genetic analysis has revealed that Runx2 is degraded through a Smurf-mediated ubiquitination pathway, and its activity is inhibited by HDAC4 [17].
• Smurf1 has been shown to interact with Smads 1, 5, 6, and 7, and Smads 1 and 5 also interact with Runx2 [7].
• LIM mineralization protein-1 potentiates bone morphogenetic protein responsiveness via a novel interaction with Smurf1 resulting in decreased ubiquitination of Smads [8].
• It has been reported that Smurf1, a member of the Hect family E3 ubiquitin ligases, can target Smad1 to 26S proteasome for degradation [18].

References