Regulation of Smad4 sumoylation and transforming growth factor-beta signaling by protein inhibitor of activated STAT1.
The tumor suppressor, Smad4/DPC4, is a common signal transducer in transforming growth factor-beta (TGF-beta) signaling. In this study, we demonstrated that the protein inhibitor of activated STAT1 (PIAS1) regulates the signaling potential of Smad4 through a sumoylation-dependent mechanism. PIAS1 was shown to be an E3 ligase for Smad4 sumoylation in vitro and in vivo. PIAS1 physically interacted with Smad4 in a TGF-beta-inducible manner. A minimal SUMO E3 ligase domain and Smad4-binding domain were defined on PIAS1 protein. The RING finger domain of PIAS1 was essential for its E3 ligase function. Although PIAS1 enhanced the Smad4-dependent transcriptional activation of TGF-beta signaling, a mutant lacking the RING domain inhibited the sumoylation of Smad4 in a dominant negative manner and, as a result, abolished the transcriptional response of TGF-beta. These data demonstrate that PIAS1 protein positively modulates TGF-beta responses as a SUMO E3 ligase for Smad4.
Liang
Min
M
Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA.
Melchior
Frauke
F
Feng
Xin-Hua
XH
Lin
Xia
X
D000818:Animals; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D050828:Protein Inhibitors of Activated STAT; D011506:Proteins / Q000378:metabolism*; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D051901:Smad4 Protein; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D004268:DNA-Binding Proteins; D050828:Protein Inhibitors of Activated STAT; D011506:Proteins; C497796:SMAD4 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D051901:Smad4 Protein; D025841:Small Ubiquitin-Related Modifier Proteins; D015534:Trans-Activators; D016212:Transforming Growth Factor beta