2020
DOI: 10.1096/fj.202000306r
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PAR1&2driven placenta EVT invasion act via LRP5/6 as coreceptors

Abstract: While the involvement of protease-activated receptors (PARs) in the physiological regulation of human placenta development, as in tumor biology, is recognized, the molecular pathway is unknown. We evaluated the impact of PAR 1 and PAR 2 function in cytotrophoblast (CTB) proliferation and invasion in a system of extravillous trophoblast (EVT) organ culture and in human cell-lines. Activation of PAR 1-and PAR 2-induced EVT invasion and proliferation, while the shRNA silencing of lowdensity lipoprotein receptor-r… Show more

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Cited by 4 publications
(6 citation statements)
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“…In a similar manner, the PAR1 mutant hPar1-7A is also unable to associate with the PH domain and significantly reduces breast cancer progression and EVT invasion. Moreover, very recently, Grisaru-Granovsky et al evaluated the impact of PAR1 and PAR2 on physiological EVT invasion for early placenta development by demonstrating that PAR2 is necessary and required for PAR1-induced β-catenin stabilization through the formation of PAR-LPR5/6-Axin complex, paralleling the Wnt signaling pathway in an independent manner [ 290 ]. These findings indicate the significance of PAR PH domain binding motifs in both pathological and normal invasion processes.…”
Section: Cancer-associated Gpcr-mediated Signaling Pathwaysmentioning
confidence: 99%
“…In a similar manner, the PAR1 mutant hPar1-7A is also unable to associate with the PH domain and significantly reduces breast cancer progression and EVT invasion. Moreover, very recently, Grisaru-Granovsky et al evaluated the impact of PAR1 and PAR2 on physiological EVT invasion for early placenta development by demonstrating that PAR2 is necessary and required for PAR1-induced β-catenin stabilization through the formation of PAR-LPR5/6-Axin complex, paralleling the Wnt signaling pathway in an independent manner [ 290 ]. These findings indicate the significance of PAR PH domain binding motifs in both pathological and normal invasion processes.…”
Section: Cancer-associated Gpcr-mediated Signaling Pathwaysmentioning
confidence: 99%
“…Previously, we have demonstrated that PAR 1 or PAR 2 oncogenes are potent inducers of nuclear β‐catenin localization acting via recruitment of LRP5/6 coreceptors in both the malignant and physiological invasion process of placenta anchorage to the uterus decidua 17–20 . PAR 2 ‐induced β‐catenin stabilization was observed in the presence of Wnt/FZD inhibitors; either the Wnt porcupine inhibitor LGK 974 or in the presence of secreted frizzled‐related protein (sFRP); a FZD inhibitor (Figures S1–S3, respectively).…”
Section: Resultsmentioning
confidence: 91%
“…Although PAR 1 or PAR 2 ‐induced nuclear localization of β‐catenin and its co‐transcriptional downstream gene signature activity has been demonstrated, essential key regulators that govern PAR‐induced β‐catenin path are unknown. We have previously studied the causal relationship between PAR and nuclear localization of β‐catenin in a transgenic mouse line overexpressing PAR 1 in the mammary glands and in several established epithelial tumor cell lines of intact β‐catenin system 17–20 . To gain further insight into the posttranslational control of PAR 2 in colon cancer growth and development we set out to evaluate the role in RNF43 on PAR 2 ‐induced colon cancer settings.…”
Section: Introductionmentioning
confidence: 99%
“…Whereas the evolving role of PARs in tumor advancement has been acknowledged, their underlying molecular mechanism and their signaling-induced post-translational regulation remain elusive. We have previously shown that either PAR 1 or PAR 2 oncogenes are effective inducers of β-catenin stabilization, acting via recruitment of LRP5/6 coreceptors in both the malignant and the physiological invasion of placenta anchorage to the uterus decidua [ 16 , 17 , 18 , 19 , 20 ]. PAR 2 was attributed a dominant role over PAR 1 [ 19 , 21 ], while PAR 3 functions mainly as a coreceptor.…”
Section: Introductionmentioning
confidence: 99%
“…We have previously shown that either PAR 1 or PAR 2 oncogenes are effective inducers of β-catenin stabilization, acting via recruitment of LRP5/6 coreceptors in both the malignant and the physiological invasion of placenta anchorage to the uterus decidua [ 16 , 17 , 18 , 19 , 20 ]. PAR 2 was attributed a dominant role over PAR 1 [ 19 , 21 ], while PAR 3 functions mainly as a coreceptor. PAR 4 is a receptor for thrombin-induced human platelets along with PAR 1 [ 22 , 23 ].…”
Section: Introductionmentioning
confidence: 99%