TY - JOUR
T1 - Protease-activated receptor-1 (PAR1) acts via a novel Gα 13-dishevelled axis to stabilize β-catenin levels
AU - Turm, Hagit
AU - Maoz, Myriam
AU - Katz, Vered
AU - Yin, Yong Jun
AU - Offermanns, Steffan
AU - Bar-Shavit, Rachel
PY - 2010/5/14
Y1 - 2010/5/14
N2 - We have previously shown a novel link between hPar-1 (human protease-activated receptor-1) and β-catenin stabilization. Although it is well recognized that Wnt signaling leads to β-catenin accumulation, the role of PAR1 in the process is unknown. We provide here evidence that PAR1 induces β-catenin stabilization independent of Wnt, Fz (Frizzled), and the co-receptor LRP5/6 (low density lipoprotein-related protein 5/6) and identify selective mediators of the PAR1-β-catenin axis. Immunohistological analyses of hPar1-transgenic (TG) mouse mammary tissues show the expression of both Gα12 and Gα13 compared with age-matched control counterparts. However, only Gα13 was found to be actively involved in PAR1-induced β-catenin stabilization. Indeed, a dominant negative form of Gα13 inhibited both PAR1-induced Matrigel invasion and Lef/ Tcf (lymphoid enhancer factor/T cell factor) transcription activity. PAR1-Gα13 association is followed by the recruitment of DVL (Dishevelled), an upstream Wnt signaling protein via the DIX domain. Small interfering RNA-Dvl silencing leads to a reduction in PAR1-induced Matrigel invasion, inhibition of Lef/Tcf transcription activity, and decreased β-catenin accumulation. It is of note that PAR1 also promotes the binding of β-arrestin-2 to DVL, suggesting a role for β-arrestin-2 in PAR1-induced DVL phosphorylation dynamics. Although infection of small interfering RNA-LRP5/6 or the use of the Wnt antagonists, SFRP2 (soluble Frizzled-related protein 2) or SFRP5 potently reduced Wnt3A-mediated β-catenin accumulation, no effect was observed on PAR1-induced β-catenin stabilization. Collectively, our data show that PAR1 mediates β-catenin stabilization independent of Wnt. We propose here a novel cascade of PAR1-induced Gα13-DVL axis in cancer and β-catenin stabilization.
AB - We have previously shown a novel link between hPar-1 (human protease-activated receptor-1) and β-catenin stabilization. Although it is well recognized that Wnt signaling leads to β-catenin accumulation, the role of PAR1 in the process is unknown. We provide here evidence that PAR1 induces β-catenin stabilization independent of Wnt, Fz (Frizzled), and the co-receptor LRP5/6 (low density lipoprotein-related protein 5/6) and identify selective mediators of the PAR1-β-catenin axis. Immunohistological analyses of hPar1-transgenic (TG) mouse mammary tissues show the expression of both Gα12 and Gα13 compared with age-matched control counterparts. However, only Gα13 was found to be actively involved in PAR1-induced β-catenin stabilization. Indeed, a dominant negative form of Gα13 inhibited both PAR1-induced Matrigel invasion and Lef/ Tcf (lymphoid enhancer factor/T cell factor) transcription activity. PAR1-Gα13 association is followed by the recruitment of DVL (Dishevelled), an upstream Wnt signaling protein via the DIX domain. Small interfering RNA-Dvl silencing leads to a reduction in PAR1-induced Matrigel invasion, inhibition of Lef/Tcf transcription activity, and decreased β-catenin accumulation. It is of note that PAR1 also promotes the binding of β-arrestin-2 to DVL, suggesting a role for β-arrestin-2 in PAR1-induced DVL phosphorylation dynamics. Although infection of small interfering RNA-LRP5/6 or the use of the Wnt antagonists, SFRP2 (soluble Frizzled-related protein 2) or SFRP5 potently reduced Wnt3A-mediated β-catenin accumulation, no effect was observed on PAR1-induced β-catenin stabilization. Collectively, our data show that PAR1 mediates β-catenin stabilization independent of Wnt. We propose here a novel cascade of PAR1-induced Gα13-DVL axis in cancer and β-catenin stabilization.
UR - http://www.scopus.com/inward/record.url?scp=77952047728&partnerID=8YFLogxK
U2 - 10.1074/jbc.M109.072843
DO - 10.1074/jbc.M109.072843
M3 - Article
C2 - 20223821
AN - SCOPUS:77952047728
SN - 0021-9258
VL - 285
SP - 15137
EP - 15148
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 20
ER -