摘要
The Rho family of GTPases is strictly regulated by a large family of GTPase-activating proteins(GAPs)that stimulate the relatively weak intrinsic GTP-hydrolyzing activity of Rho GTPases.p190A is a potent and widely expressed GAP that acts on RhoA GTPases.p190A is frequently mutated in endometrial cancer,but the contribution of p190A mutations to endometrial tumorigenesis remains unclear.Here we identified that p190A is an upstream regulator of the Hippo-YAP signaling pathway,which is a critical regulator of cell proliferation,apoptosis,and cell fate.p190A knockout in endometrial cancer cells promoted cell proliferation,migration,and epithelial–mesenchymal transition(EMT),which were partially dependent on YAP activation.Wild-type p190A,but not endometrial cancer-associated mutants,suppressed the nuclear localization,transcriptional activity,and malignant transformation function of YAP.Moreover,the nuclear localization of YAP was enhanced in p190A-mutated endometrial cancer.These findings reveal novel molecular mechanisms underlying Hippo-YAP pathway-driven endometrial tumorigenesis and elucidate the potential for therapy targeting the Hippo-YAP pathway in p190A-mutated endometrial cancer.
基金
supported by the National Natural Science Foundation of China(numbers 91954106 and 81872109 to K.G.,number 81672574 to X.W.,and number 81601247 to B.L.)
the Shanghai Municipal Medical and Health Discipline Construction Projects(number 2017ZZ02015 to X.W.)
the Natural Science Foundation of Shanghai(number 18ZR1430100 to K.G.)
the Shanghai Clinical Medicine Field Project of Science and Technology Innovation Action Program(number 17411951600 to X.W.).
