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| Content Provider | Springer Nature Link |
|---|---|
| Author | Jaber, Mohammad Maoz, Miriam Kancharla, Arun Agravich, Daniel Peretz, Tamar Grisaru Gravsky, Sorina Uziely, Beatrice Bar Shavit, Rachel |
| Copyright Year | 2013 |
| Abstract | Mammalian protease-activated-receptor-1 and -2 (PAR1 and PAR2) are activated by proteases found in the flexible microenvironment of a tumor and play a central role in breast cancer. We propose in the present study that PAR1 and PAR2 act together as a functional unit during malignant and physiological invasion processes. This notion is supported by assessing pro-tumor functions in the presence of short hairpin; shRNA knocked-down hPar2 or by the use of a truncated PAR2 devoid of the entire cytoplasmic tail. Silencing of hPar2 by shRNA-attenuated thrombin induced PAR1 signaling as recapitulated by inhibiting the assembly of Etk/Bmx or Akt onto PAR1-C-tail, by thrombin-instigated colony formation and invasion. Strikingly, shRNA-hPar2 also inhibited the TFLLRN selective PAR1 pro-tumor functions. In addition, while evaluating the physiological invasion process of placenta extravillous trophoblast (EVT) organ culture, we observed inhibition of both thrombin or the selective PAR1 ligand; TFLLRNPNDK induced EVT invasion by shRNA-hPar2 but not by scrambled shRNA-hPar2. In parallel, when a truncated PAR2 was utilized in a xenograft mouse model, it inhibited PAR1–PAR2-driven tumor growth in vivo. Similarly, it also attenuated the interaction of Etk/Bmx with the PAR1-C-tail in vitro and decreased markedly selective PAR1-induced Matrigel invasion. Confocal images demonstrated co-localization of PAR1 and PAR2 in HEK293T cells over-expressing YFP-hPar2 and HA-hPar1. Co-immuno-precipitation analyses revealed PAR1-PAR2 complex formation but no PAR1-CXCR4 complex was formed. Taken together, our observations show that PAR1 and PAR2 act as a functional unit in tumor development and placenta-uterus interactions. This conclusion may have significant consequences on future breast cancer therapeutic modalities and improved late pregnancy outcome. |
| Starting Page | 2517 |
| Ending Page | 2533 |
| Page Count | 17 |
| File Format | |
| ISSN | 1420682X |
| Journal | Cellular and Molecular Life Sciences |
| Volume Number | 71 |
| Issue Number | 13 |
| e-ISSN | 14209071 |
| Language | English |
| Publisher | Springer Basel |
| Publisher Date | 2013-11-01 |
| Publisher Place | Basel |
| Access Restriction | Subscribed |
| Subject Keyword | PAR1 PAR2 Protease GPCR Thrombin Breast tumor Cell Biology Biomedicine general Life Sciences Biochemistry |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Molecular Biology Molecular Medicine Pharmacology Cellular and Molecular Neuroscience |
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