SPSB1, a Novel Negative Regulator of the TGF-{beta} Signaling Pathway Targeting the Type II Receptor [Molecular Bases of Disease]

June 1st, 2015 by Liu, S., Nheu, T., Luwor, R., Nicholson, S. E., Zhu, H.-J.

Appropriate cellular signaling is essential to control cell proliferation, differentiation and cell death. Aberrant signaling can have devastating consequences and lead to disease states including cancer. The transforming growth factor-β (TGF-β) signaling pathway is a prominent signaling pathway that has been tightly regulated in normal cells while its deregulation strongly correlates with the progression of human cancers. The regulation of the TGF-β signaling pathway involves a variety of physiological regulators. Many of these molecules act to alter the activity of Smad proteins. In contrast, the number of molecules known to affect TGF-β signaling pathway at the receptor level is relatively low and there are no known direct modulators for the TGF-β type II receptor (TβRII). Here we identify SPSB1 (a SPRY domain-containing SOCS box protein) as a novel regulator of the TGF-β signaling pathway. SPSB1 negatively regulates TGF-β signaling pathway through its interaction with both endogenous and over-expressed TβRII (and not TβRI) via its SPRY domain. As such, TβRII and SPSB1 colocalize on the cell membrane. SPSB1 maintains TβRII at a low level by enhancing the ubiquitination levels and degradation rates of TβRII through its SOCS box. More importantly, silencing SPSB1 by siRNA results in enhanced TGF-β signaling and migration and invasion of tumor cells.