PMID- 23618389
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20130517
LR  - 20240321
IS  - 1478-811X (Print)
IS  - 1478-811X (Electronic)
IS  - 1478-811X (Linking)
VI  - 11
IP  - 1
DP  - 2013 Apr 24
TI  - The role of LPA and YAP signaling in long-term migration of human ovarian cancer 
      cells.
PG  - 31
LID - 10.1186/1478-811X-11-31 [doi]
AB  - BACKGROUND: The 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. RESULTS: We 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. CONCLUSIONS: A 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.
FAU - Cai, Hui
AU  - Cai H
AD  - Department of Obstetrics and Gynecology, Indiana University School of Medicine, 
      975 W, Walnut St, IB355A, Indianapolis, IN 46202, USA. xu2@iupui.edu.
FAU - Xu, Yan
AU  - Xu Y
LA  - eng
PT  - Journal Article
DEP - 20130424
PL  - England
TA  - Cell Commun Signal
JT  - Cell communication and signaling : CCS
JID - 101170464
EIN - Cell Commun Signal. 2013;11:92
PMC - PMC3655373
EDAT- 2013/04/27 06:00
MHDA- 2013/04/27 06:01
PMCR- 2013/04/24
CRDT- 2013/04/27 06:00
PHST- 2013/01/10 00:00 [received]
PHST- 2013/04/09 00:00 [accepted]
PHST- 2013/04/27 06:00 [entrez]
PHST- 2013/04/27 06:00 [pubmed]
PHST- 2013/04/27 06:01 [medline]
PHST- 2013/04/24 00:00 [pmc-release]
AID - 1478-811X-11-31 [pii]
AID - 10.1186/1478-811X-11-31 [doi]
PST - epublish
SO  - Cell Commun Signal. 2013 Apr 24;11(1):31. doi: 10.1186/1478-811X-11-31.