The role of LPA and YAP signaling in long-term migration of human ovarian cancer cells

Abstract

BackgroundThe Hippo-YAP signaling pathway is altered and implicated as oncogenic in many human cancers. However, extracellular signals that regulate the mammalian Hippo pathway have remained elusive until very recently when it was shown that the Hippo pathway is regulated by G-protein-coupled receptor (GPCR) ligands including lysophosphatidic acid (LPA) and sphingosine 1-phosphophate (S1P). LPA inhibits Lats kinase activity in HEK293 cells, but the potential involvement of a protein phosphatase was not investigated. The extracellular regulators of YAP dephosphorylation (dpYAP) and nuclear translocation in epithelial ovarian cancer (EOC) are essentially unknown.ResultsWe showed here that LPA dose- and time-dependently induced dpYAP in human EOC cell lines OVCA433, OVCAR5, CAOV3, and Monty-1, accompanied by increased YAP nuclear translocation. YAP was involved in LPA-induced migration and invasion of EOC cells and LPA3 was a major LPA receptor mediating the migratory effect. We demonstrated that G13, but not or to a lesser extent G12, Gi or Gq, was necessary for LPA-induced dpYAP and its nuclear translocation and that RhoA-ROCK, but not RhoB, RhoC, Rac1, cdc42, PI3K, ERK, or AKT, were required for the LPA-dpYAP effect. In contrast to results in HEK293 cells, LPA did not inhibit Mst and Lats kinase in OVCA433 EOC cells. Instead, protein phosphatase 1A (PP1A) acted down-stream of RhoA in LPA-induction of dpYAP. In addition, we identified that amphiregulin (AREG), a down-stream target of YAP which activated EGF receptors (EGFR), mediated an LPA-stimulated and EGFR-dependent long-term (16 hr) cell migration. This process was transcription- and translation-dependent and was distinct from a transcription- and YAP-independent short-term (4 hr) cell migration. EOC tissues had reduced pYAP levels compared to normal and benign ovarian tissues, implying the involvement of dpYAP in EOC pathogenesis, as well as its potential marker and/or target values.ConclusionsA novel LPA-LPA3-G13-RhoA-ROCK-PP1A-dpYAP-AREG-EGFR signaling pathway was linked to LPA-induced migration of EOC cells. Reduced pYAP levels were demonstrated in human EOC tumors as compared to both normal ovarian tissues and benign gynecologic masses. Our findings support that YAP is a potential marker and target for developing novel therapeutic strategies against EOC.

RASSF1A Suppresses the Invasion and Metastatic Potential of Human Non–Small Cell Lung Cancer Cells by Inhibiting YAP Activation through the GEF-H1/RhoB Pathway

“…Such promigratory effect could be attributed in part to the increase of YAP transcriptional activity in RASSF1A-depleted cells. YAP promigratory effects have been already reported in ovarian cancer cells treated by LPA (34) or in Drosophila border cells migration (35). In line with such data, we report here that RASSF1A knockdown promotes a nuclear accumulation of active YAP.…”

Serum deprivation inhibits the transcriptional co-activator YAP and cell growth via phosphorylation of the 130-kDa isoform of Angiomotin by the LATS1/2 protein kinases

“…Here the levels of Amot130, but not AmotL1, are shown to directly respond to serum starvation through phosphorylation by LATS, which in turn is a critical event for Hippo-induced growth arrest. Future experiments examining other inhibitors of YAP, such as PP1 (38), glucagon, and epinephrine (2), for their effects on Amot130 phosphorylation may further establish how this event is central to Hippo signaling.…”

Netrin-1 exerts oncogenic activities through enhancing Yes-associated protein stability

“…It is reported that PP1A acts downstream of RhoA in LPA-induced YAP dephosphoryaltion (25) and PI3K and ERK1/2 signaling is involved in the regulation of PP1A activity in cancer cells (26,27). Conceivably, netrin-1 elevates YAP stability through regulating PP1A activity induced by the signaling transduced from the binding of netrin and its receptors.…”