STAT3 integrates cooperative Ras and TGF-β signals that induce Snail expression

Abstract

The epithelial-mesenchymal transition (EMT) is a crucial morphological event that occurs during the progression of epithelial tumors. EMT can be induced by transforming growth factor β (TGF-β) in certain kinds of cancer cells through the induction of Snail, a key regulator of EMT. We have previously found that TGF-β remarkably induces Snail expression in cooperation with Ras signals; however, the underlying mechanism of this synergism has not yet been determined. Here, we demonstrate that signal transducer and activator of transcription 3 (STAT3) acts as a mediator that synergizes TGF-β and Ras signals. The overexpression of STAT3 enhanced Snail induction, whereas siRNA-mediated knockdown of STAT3 inhibited it. The STAT3-YF mutant, which has Tyr 705 substituted with Phe, did not enhance Snail induction. Several STAT3 mutants lacking transcriptional activity also failed to enhance it; however, the putative STAT3-binding elements in the Snail promoter regions were not required for STAT3-mediated Snail induction. Protein inhibitor of activated STAT3 (PIAS3) inhibited the enhanced Snail promoter activity induced by TGF-β and Ras. The interaction between PIAS3 and STAT3 was reduced by TGF-β in cells harboring oncogenic Ras, whereas TGF-β promoted the binding of PIAS3 to Smad3, a crucial mediator of TGF-β signaling. Therefore, these findings suggest that STAT3 enhances Snail induction when it is dissociated from PIAS3 by TGF-β in cooperation with Ras signals.

Role of Stat3 Signaling in Control of EMT of Tubular Epithelial Cells During Renal Fibrosis

“…Very recently, activated TGFβ1/SMAD3 signaling has been shown to induce phosphorylation and activation of Stat3 to promote transcription of Snail in tumors [11]. However, whether this mechanism also functions during EMT of renal TECs is unknown.…”

“…This specific function of Stat3 was supported by the factors that several Stat3 mutants lacking transcriptional activity failed to enhance Snail transcription but the wildtype Stat3 did, and Stat3 appeared to enhance Snail induction via its dissociation from Protein inhibitor of activated STAT3 (PIAS3) by TGFβ1 in cooperation with Ras signals [11]. Moreover, activated Stat3 is known to be a potent activator of Snail, through a variety of mechanisms [11, 14-16]. Since we detected upregulation of pStat3 in the injured kidney, we tried to figure out a direct link between SMAD3 signaling and Stat3 activation as well as Snail expression in the current study.…”

“…Finally, we examined whether the recent report about activation of Snail in tumors by TGFβ/SMAD3/Stat3 may be also function in renal TECs [11]. Primary mouse TECs were treated with TGFβ1 and a specific SMAD3 phosphorylation inhibitor (SIS3), or a specific Stat3 phosphorylation inhibitor NSC74859.…”

“…However, the exact molecular signaling that regulates activation of EMT-associated genes by phosphorylation of SMAD3 has not been elucidated. Very recently, activated TGFβ1/SMAD3 signaling has been shown to induce phosphorylation and activation of signal transducer and activator of transcription 3 (Stat3) to promote transcription of Snail in tumors [11]. However, whether this mechanism also functions during EMT of renal TECs is unknown.…”

Efficacy of ALK5 inhibition in myelofibrosis

“…Collectively, galunisertib treatment effectively inhibits the intrinsically elevated ALK5/ Smad3 pathway, leading to a diminution in collagen production by abnormal MSCs. Interestingly, we also observed decreased p-STAT3 by TGF-β blockade, which may result from the modulation of interacting pathways (62,63) important for regulation of collagen production and inflammation related to IL-6 (64).…”