Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a Trio-regulated Rho GTPase Signaling Circuitry

Xiaodong Feng, Maria Sol Degese, Ramiro Iglesias-Bartolome, Jose P. Vaque, Alfredo A. Molinolo, Murilo Rodrigues, M. Raza Zaidi, Bruce R. Ksander, Glenn Merlino, Akrit Sodhi, Qianming Chen, J. Silvio Gutkind

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)831-845
Number of pages15
JournalCancer cell
Volume25
Issue number6
DOIs
StatePublished - Jun 16 2014

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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  • Cite this

    Feng, X., Degese, M. S., Iglesias-Bartolome, R., Vaque, J. P., Molinolo, A. A., Rodrigues, M., Zaidi, M. R., Ksander, B. R., Merlino, G., Sodhi, A., Chen, Q., & Gutkind, J. S. (2014). Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a Trio-regulated Rho GTPase Signaling Circuitry. Cancer cell, 25(6), 831-845. https://doi.org/10.1016/j.ccr.2014.04.016