Smurf control in bone cells

Abstract

The homologous to the E6-associated protein carboxyl terminus (HECT) domain E3 ubiquitin ligase Smurf1 is the first E3 ligase to be implicated in regulating bone cell function. The involvement of Smurf1 in multiple signaling pathways and pathological conditions is presently an area of extensive scientific interest. This review highlights recent works exploring Smurf-regulated biological processes in bone cells and highlights recent discoveries surrounding the regulatory mechanisms modulating its catalytic activity and substrate recognition capability. Moreover, we discuss the relevance of targeting the HECT E3s through the development of small-molecule inhibitors as an anticancer therapeutic strategy.

Fig. 1

Smurf1 promotes ubiquitination and proteasome degradation of TAK1 protein. A: TAK1 protein levels were determined in bone marrow stromal cells from wild-type and Smurf1^−/− mice by Western blot analysis. B: Overexpression of wild-type but not Smurf1 catalytic mutant reduces TAK1 protein levels in 293T cells, which are co-transfected with Smurf1 and TAK1 expression vectors. C: Smurf1 increases ubiquitin conjugated TAK1 in the presence of proteasome inhibitor MG132 in 293T cells.

Fig. 2

Smurf1 regulates osteoblast function. A: In osteoblasts and precursors, under normal condition, Smurf1 negatively regulates osteoblast differentiation by limiting the accumulation of BMP Smad, Runx2, and JunB protein in the cytoplasm through proteasome degradation. B: In chronic inflammation where systemic cytokine levels are elevated, Smurf1-medaited protein degradation is increased due to increased expression or activity of Smurf1 and modified substrate sensitivity for ubiquitination, leading to reduced levels of these positive osteoblast factors in the cytoplasm and reduced transcription of osteoblast-specific genes.