Smad1 stabilization and delocalization in response to the blockade of BMP activity

Abstract

Signaling at the plasma membrane receptors is generally terminated by some form of feedback regulation, such as endocytosis and/or degradation of the receptors. BMP-Smad1 signaling can also be attenuated by BMP-induced expression of the inhibitory Smads, which are negative regulators of Smad1 transactivation activity and/or BMP antagonists. Here, we report on a novel Smad1 regulation mechanism that occurs in response to the blockade of BMP activity. Lowering the serum levels or antagonizing BMPs with noggin led to upregulation of Smad1 at the protein level in several cell lines, but not to upregulation of Smad5, Smad8 or Smad2/3. The Smad1 upregulation occurs at the level of protein stabilization. Upregulated Smad1 was relocalized to the perinuclear region. These alterations seem to affect the dynamics and amplitude of BMP2-induced Smad1 reactivation. Our findings indicate that depleting or antagonizing BMPs leads to Smad1 stabilization and relocalization, thus revealing an unexpected regulatory mechanism for BMP-Smad1 signaling.

Reversely immortalized mouse salivary gland cells presented a promising metabolic and fibrotic response upon BMP9/Gdf2 stimulation

“…ActrII, BmprIa , and BmprII were expressed, while AcrrIIb , BmprIb , Alk1 , and Alk2 were detected at extremely low levels (data not shown). Phosphorylation of SMAD1/5/8 promotes SMAD4 translocation to the nucleus, followed by the activation of SMAD-response elements [ 50 ]. A relatively low mRNA level of S mad8 was detected in iSMGCs and iSLGCs, which increased following BMP9 stimulation.…”