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Urokinase-type Plasminogen Activator (uPA) Promotes Angiogenesis by Attenuating Proline-rich Homeodomain Protein (PRH) Transcription Factor Activity and De-repressing Vascular Endothelial Growth Factor (VEGF) Receptor Expression
| Content Provider | Scilit |
|---|---|
| Author | Stepanova, Victoria Jayaraman, Padma-Sheela Zaitsev, Sergei V. Lebedeva, Tatiana Bdeir, Khalil Kershaw, Rachael Holman, Kelci R. Parfyonova, Yelena V. Semina, Ekaterina V. Beloglazova, Irina B. Tkachuk, Vsevolod A. Cines, Douglas B. |
| Copyright Year | 2016 |
| Description | Journal: Journal of Biological Chemistry Urokinase-type plasminogen activator (uPA) regulates angiogenesis and vascular permeability through proteolytic degradation of extracellular matrix and intracellular signaling initiated upon its binding to uPAR/CD87 and other cell surface receptors. Here, we describe an additional mechanism by which uPA regulates angiogenesis. Ex vivo VEGF-induced vascular sprouting from Matrigel-embedded aortic rings isolated from uPA knock-out $(uPA^{−/−}$) mice was impaired compared with vessels emanating from wild-type mice. Endothelial cells isolated from $uPA^{−/−}$ mice show less proliferation and migration in response to VEGF than their wild type counterparts or $uPA^{−/−}$ endothelial cells in which expression of wild type uPA had been restored. We reported previously that uPA is transported from cell surface receptors to nuclei through a mechanism that requires its kringle domain. Intranuclear uPA modulates gene transcription by binding to a subset of transcription factors. Here we report that wild type single-chain uPA, but not uPA variants incapable of nuclear transport, increases the expression of cell surface VEGF receptor 1 (VEGFR1) and VEGF receptor 2 (VEGFR2) by translocating to the nuclei of ECs. Intranuclear single-chain uPA binds directly to and interferes with the function of the transcription factor hematopoietically expressed homeodomain protein or proline-rich homeodomain protein (HHEX/PRH), which thereby lose their physiologic capacity to repress the activity of vehgr1 and vegfr2 gene promoters. These studies identify uPA-dependent de-repression of vegfr1 and vegfr2 gene transcription through binding to HHEX/PRH as a novel mechanism by which uPA mediates the pro-angiogenic effects of VEGF and identifies a potential new target for control of pathologic angiogenesis. |
| Related Links | http://www.jbc.org/content/291/29/15029.full.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4946921/pdf http://www.jbc.org/article/S0021925820412517/pdf |
| Ending Page | 15045 |
| Page Count | 17 |
| Starting Page | 15029 |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| DOI | 10.1074/jbc.m115.678490 |
| Journal | Journal of Biological Chemistry |
| Issue Number | 29 |
| Volume Number | 291 |
| Language | English |
| Publisher | Elsevier BV |
| Publisher Date | 2016-07-01 |
| Access Restriction | Open |
| Subject Keyword | Journal: Journal of Biological Chemistry Prh/hhex Transcription Factor Nuclear Translocation Urokinase Plasminogen Activator Vascular Endothelial Growth Factor (vegf) |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
