Ubiquitin Ligase Smurf1 Controls Osteoblast Activity and Bone Homeostasis by Targeting MEKK2 for Degradation

Abstract

Bone is constantly resorbed and formed throughout life by coordinated actions of osteoclasts and osteoblasts. Here we show that Smurf1, a HECT domain ubiquitin ligase, has a specific physiological role in suppressing the osteogenic activity of osteoblasts. Smurf1-deficient mice are born normal but exhibit an age-dependent increase of bone mass. The cause of this increase can be traced to enhanced activities of osteoblasts, which become sensitized to bone morphogenesis protein (BMP) in the absence of Smurf1. However, loss of Smurf1 does not affect the canonical Smad-mediated intracellular TGFbeta or BMP signaling; instead, it leads to accumulation of phosphorylated MEKK2 and activation of the downstream JNK signaling cascade. We demonstrate that Smurf1 physically interacts with MEKK2 and promotes the ubiquitination and turnover of MEKK2. These results indicate that Smurf1 negatively regulates osteoblast activity and response to BMP through controlling MEKK2 degradation.

Regulation of Smad activities

“…To this end, dSmurf, the Drosophila Smurf, was shown to restrict DPP signaling during Drosophila embryonic development, supporting the idea that by targeting R-Smads for degradation dSmurf is a negative regulator of TGF-β signaling in vivo [92]. In contrast, knockout of the Smurf1 gene in mice did not manifest phenotypes that implicate Smurf1 function in R-Smads degradation [93]. Rather, Smurf1 appeared to be a critical regulator of the abundance of MEKK2 [93].…”

The p38α MAPK positively regulates osteoblast function and postnatal bone acquisition

“…Another transcription factor, Atf4 regulates bone matrix deposition by mature osteoblasts [25]. Furthermore, several signaling pathways have been shown to regulate postnatal osteoblast function including Ihh [26], Wnt/Lrp5 [27], TGFb-BMP/Smads [28][29][30], BMP/MEKK2/MEK5-7/Jnk [31], b-adrenergic [32], IGF-1 [16], insulin [33] and PTH signaling [34]. The p38 MAPK pathway has been recently shown to be an essential regulator of osteoblastogenesis during skeletogenesis [12,13].…”

Stk38 protein kinase preferentially inhibits TLR9-activated inflammatory responses by promoting MEKK2 ubiquitination in macrophages

“…E3 ubiquitin ligase Smurf1 inhibits MEKK2 expression by catalysing K48-linked ubiquitination of MEKK2 (ref. 24). We explored whether Stk38 affected the regulation of MEKK2 expression by Smurf1.…”