TY - JOUR
T1 - Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a Trio-regulated Rho GTPase Signaling Circuitry
AU - Feng, Xiaodong
AU - Degese, Maria Sol
AU - Iglesias-Bartolome, Ramiro
AU - Vaque, Jose P.
AU - Molinolo, Alfredo A.
AU - Rodrigues, Murilo
AU - Zaidi, M. Raza
AU - Ksander, Bruce R.
AU - Merlino, Glenn
AU - Sodhi, Akrit
AU - Chen, Qianming
AU - Gutkind, J. Silvio
N1 - Funding Information:
We acknowledge the extensive support, guidance, and help from all members of the J.S.G. laboratory and the Oral Cancer Branch for their generous contributions and thoughtful suggestions throughout these studies. We thank Dr. Thomas Bugge and Dr. Marius Sudol for insightful advice and critically reading our manuscript. We thank Dr. James T. Handa and Dr. Shannath Merbs, Wilmer Eye Institute, Johns Hopkins School of Medicine, for generously providing snap-frozen uveal melanoma tissue. This research was partially supported by the Intramural Research Program of NIH, National Institute of Dental and Craniofacial Research. We apologize to all of our colleagues for not citing some of their original studies because of space limitations.
PY - 2014/6/16
Y1 - 2014/6/16
N2 - Mutually exclusive activating mutations in the GNAQ and GNA11 oncogenes, encoding heterotrimeric Gαq family members, have been identified in ~83% and ~6% of uveal and skin melanomas, respectively. However, the molecular events underlying these GNAQ-driven malignancies are not yet defined, thus limiting the ability to develop cancer-targeted therapies. Here, we focused on the transcriptional coactivator YAP, a critical component of the Hippo signaling pathway that controls organ size. We found that Gαq stimulates YAP through a Trio-Rho/Rac signaling circuitry promoting actin polymerization, independently of phospholipase Cβ and the canonical Hippo pathway. Furthermore, we show that Gαq promotes the YAP-dependent growth of uveal melanoma cells, thereby identifying YAP as a suitable therapeutic target in uveal melanoma, a GNAQ/. GNA11-initiated human malignancy. •The GNAQ oncogene stimulates the transcriptional coactivator YAP in uveal melanoma•A Hippo- and PLCβ-independent Rho GTPase signaling circuitry links GNAQ to YAP•YAP is essential for GNAQ-induced uveal melanoma cell proliferation•YAP represents a suitable therapeutic target for melanomas harboring GNAQ mutations. Feng etal. find that aberrant Gαq/11 activation due to oncogenic mutations leads to YAP-dependent growth in uveal melanoma. In this context, YAP stimulation is independent of PLCβ and the canonical Hippo pathway and instead acts through Trio-Rho/Rac signaling and actin polymerization.
AB - Mutually exclusive activating mutations in the GNAQ and GNA11 oncogenes, encoding heterotrimeric Gαq family members, have been identified in ~83% and ~6% of uveal and skin melanomas, respectively. However, the molecular events underlying these GNAQ-driven malignancies are not yet defined, thus limiting the ability to develop cancer-targeted therapies. Here, we focused on the transcriptional coactivator YAP, a critical component of the Hippo signaling pathway that controls organ size. We found that Gαq stimulates YAP through a Trio-Rho/Rac signaling circuitry promoting actin polymerization, independently of phospholipase Cβ and the canonical Hippo pathway. Furthermore, we show that Gαq promotes the YAP-dependent growth of uveal melanoma cells, thereby identifying YAP as a suitable therapeutic target in uveal melanoma, a GNAQ/. GNA11-initiated human malignancy. •The GNAQ oncogene stimulates the transcriptional coactivator YAP in uveal melanoma•A Hippo- and PLCβ-independent Rho GTPase signaling circuitry links GNAQ to YAP•YAP is essential for GNAQ-induced uveal melanoma cell proliferation•YAP represents a suitable therapeutic target for melanomas harboring GNAQ mutations. Feng etal. find that aberrant Gαq/11 activation due to oncogenic mutations leads to YAP-dependent growth in uveal melanoma. In this context, YAP stimulation is independent of PLCβ and the canonical Hippo pathway and instead acts through Trio-Rho/Rac signaling and actin polymerization.
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U2 - 10.1016/j.ccr.2014.04.016
DO - 10.1016/j.ccr.2014.04.016
M3 - Article
C2 - 24882515
AN - SCOPUS:84902482143
VL - 25
SP - 831
EP - 845
JO - Cancer Cell
JF - Cancer Cell
SN - 1535-6108
IS - 6
ER -