P68 RNA Helicase Mediates PDGF-Induced Epithelial Mesenchymal Transition by Displacing Axin from β-Catenin

Abstract

The nuclear p68 RNA helicase (referred to as p68) is a prototypical member of the DEAD box family of RNA helicases. The protein plays a very important role in early organ development. In the present study, we characterized the tyrosine phosphorylation of p68 under platelet-derived growth factor (PDGF) stimulation. We demonstrated that tyrosine phosphorylation of p68 at Y593 mediated PDGF-stimulated epithelial-mesenchymal transition (EMT). We showed that PDGF treatment led to phosphorylation of p68 at Y593 in the cell nucleus. The Y593-phosphorylated p68 (referred to as phosphor-p68) promotes beta-catenin nuclear translocation via a Wnt-independent pathway. The phosphor-p68 facilitates beta-catenin nuclear translocation by blocking phosphorylation of beta-catenin by GSK-3beta and displacing Axin from beta-catenin. The beta-catenin nuclear translocation and subsequent interaction with the LEF/TCF was required for the EMT process. These data demonstrated a novel mechanism of phosphor-p68 in mediating the growth factor-induced EMT and uncovered a new pathway to promote beta-catenin nuclear translocation.

Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

“…One intriguing possibility is that, depending on the cellular context, ddx5/ddx17-splicing activity or their transcriptional activity could dominate each other and this could participate in the dual function of ddx5 and ddx17 in cancer. In this context, several reports have indicated that the splicing and transcriptional activities of ddx5 and ddx17 can be modulated by different post-translational modifications that depend on cellular signaling pathways (Yang et al, 2006(Yang et al, , 2007Jacobs et al, 2007;Carter et al, 2010;Mooney et al, 2010a, b). In addition, several post-translational modifications of ddx5 or ddx17 have been shown to be altered in different cancers (Causevic et al, 2001;Yang et al, 2005).…”

“…There are now many reports indicating that these multifunctional proteins have important implications for cancer development, as recently reviewed (Janknecht, 2010;FullerPace and Moore, 2011). For example, on one hand, as transcriptional coactivators of estrogen receptor alpha, they may contribute to the proliferative effect of estradiol on breast cancer cells (Wortham et al, 2009;Dutertre et al, 2010a) and, as coregulators of betacatenin, they may contribute to the epithelial to mesenchymal transition, which has been associated with breast cancer progression (Yang et al, 2006). On the other hand, as coactivators of p53 and Smad, ddx5/ ddx17 may exert tumor suppressor functions (Warner et al, 2004;Bates et al, 2005).…”

Induction and Down-regulation of Sox17 and Its Possible Roles During the Course of Gastrointestinal Tumorigenesis

“…It has also been shown that β-catenin accumulation, a hallmark of Wnt activation, is particularly enhanced in the invasion front and metastasized colon cancer cells, suggesting that promotion of Wnt/β-catenin signaling is important for malignant progression 8 . Growth factors PDGF and HGF, as well as inflammatory cytokine TNF-α, have been shown to promote Wnt/β-catenin signaling activity in tumor cells [9][10][11] .…”

Tumour–stroma interactions in colorectal cancer: converging on β-catenin activation and cancer stemness

“…Tyr phosphorylation of b-catenin leads to its stabilisation and nuclear signalling activity by decreasing its binding affinity to E-cadherin and the APC/GSKb/Axin destruction complex (Coluccia et al, 2007). Platelet-derived growth factor (PDGF) stimulation of HT-29 colorectal cancer cells increases b-catenin activation via p68-dependent inhibition of Ser/Thr phosphorylation by GSK3b (Yang et al, 2006).…”