title: SPSB1, a Novel Negative Regulator of the Transforming Growth Factor-β Signaling Pathway Targeting the Type II Receptor.
abstract: 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, whereas 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 the 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 the TGF-β signaling pathway through its interaction with both endogenous and overexpressed TβRII (and not TβRI) via its Spry domain. As such, TβRII and SPSB1 co-localize 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.
authors.affiliation: Departments of Surgery (the Royal Melbourne Hospital), University of Melbourne, Parkville, Victoria 3050, Australia; Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia.
authors.forename: Sheng
authors.initials: S
authors.lastname: Liu
authors.affiliation: Departments of Surgery (the Royal Melbourne Hospital), University of Melbourne, Parkville, Victoria 3050, Australia.
authors.forename: Thao
authors.initials: T
authors.lastname: Nheu
authors.affiliation: Departments of Surgery (the Royal Melbourne Hospital), University of Melbourne, Parkville, Victoria 3050, Australia.
authors.forename: Rodney
authors.initials: R
authors.lastname: Luwor
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia; Departments of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia.
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Nicholson
authors.affiliation: Departments of Surgery (the Royal Melbourne Hospital), University of Melbourne, Parkville, Victoria 3050, Australia. Electronic address: hongjian@unimelb.edu.au.
authors.forename: Hong-Jian
authors.initials: HJ
authors.lastname: Zhu
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D020868:Gene Silencing; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D060066:Protein Interaction Maps; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000378:metabolism*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis / Q000378:metabolism*; D015398:Signal Transduction; D050826:Suppressor of Cytokine Signaling Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D018125:Receptors, Transforming Growth Factor beta; C000602043:SPSB1 protein, human; C515022:SSB-1 protein, mouse; D050826:Suppressor of Cytokine Signaling Proteins; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: SPSB; protein degradation; receptor modification; receptor regulation; signal transduction; transforming growth factor beta (TGF-B)