Jab1 antagonizes TGF‐β signaling by inducing Smad4 degradation

Abstract

Tumor suppressor Smad4 is the common signaling effector in the transforming growth factor β (TGF-β) superfamily. Phosphorylated regulatory Smads (R-Smads) interact with Smad4, and the complex translocates into the nucleus to regulate gene transcription. Proper TGF-β signaling requires precise control of Smad functions. Smurfs have been shown to mediate the degradation of R-Smads but not the commonpartner Smad4. We report a novel mechanism of Smad4 degradation. Jab1 interacts directly with Smad4 and induces its ubiquitylation for degradation. Jab1 was initially identified as a co-activator of c-Jun, and it also induces degradation of cell cycle inhibitor p27 and tumor suppressor p53. Ectopic expression of Jab1 decreased endogenous Smad4 steady-state levels. The 26S proteasome inhibitors lactacystin and MG132 reduced the degradation rate of Smad4 protein. Examination of the effects of JAB1-induced Smad4 degradation indicates that Jab1 inhibited TGF-β-induced gene transcription. Our data suggest that Jab1 antagonizes TGF-β function by inducing degradation of Smad4 through a distinct degradation pathway.

Jab1 is overexpressed in human breast cancer and is a downstream target for HER-2/neu

“…26 In addition, Jab1 interacts directly with Smad4 and induces its degradation via the ubiquitin/ proteasome pathway which leads to attenuation of transforming growth factor-b-induced gene transcription. 27 Because transforming growth factor-b exhibits anti-cancer activity in the early stages of tumorigenesis, inhibition of transforming growth factor-b signaling pathway by Jab1 may promote tumor formation. Jab1 also binds hypoxia inducible factor-1, prevents its degradation and enhances its transcriptional activity.…”

Transcriptional Activation of Mouse Mast Cell Protease-7 by Activin and Transforming Growth Factor-β Is Inhibited by Microphthalmia-associated Transcription Factor

“…Ubiquitin ligases forming complexes with Smad2 and -3 were involved in ubiquitination and proteasomal degradation of Smad2 and -3 (44 -46). Expression of Jab1, identified as the Jun-activating domain binding protein, accelerated breakdown of Smad4 (47). Phosphorylation of Smad2 by ERK1 stabilized Smad2 protein and increased transcriptional activity of Smad2 (37).…”

Regulating the stability of TGFβ receptors and Smads

“…Stability and degradation of Smad4 are under the influence of many different E3 ligases (Figure 2). Jab1 can interact with Smad4 and induce its ubiquitination and proteasomal degradation [58]. SCF bTrCP1 is another E3 Ub ligase that has been shown to bind and catalyze ubiquitination of Smad4 [59].…”