GONUTS has been updated to MW1.31 Most things seem to be working but be sure to report problems.
PMID:23139789
| Citation |
Bruns, AF, Yuldasheva, N, Latham, AM, Bao, L, Pellet-Many, C, Frankel, P, Stephen, SL, Howell, GJ, Wheatcroft, SB, Kearney, MT, Zachary, IC and Ponnambalam, S (2012) A Heat-Shock Protein Axis Regulates VEGFR2 Proteolysis, Blood Vessel Development and Repair. PLoS ONE 7:e48539 |
|---|---|
| Abstract |
Vascular endothelial growth factor A (VEGF-A) binds to the VEGFR2 receptor tyrosine kinase, regulating endothelial function, vascular physiology and angiogenesis. However, the mechanism underlying VEGFR2 turnover and degradation in this response is unclear. Here, we tested a role for heat-shock proteins in regulating the presentation of VEGFR2 to a degradative pathway. Pharmacological inhibition of HSP90 stimulated VEGFR2 degradation in primary endothelial cells and blocked VEGF-A-stimulated intracellular signaling via VEGFR2. HSP90 inhibition stimulated the formation of a VEGFR2-HSP70 complex. Clathrin-mediated VEGFR2 endocytosis is required for this HSP-linked degradative pathway for targeting VEGFR2 to the endosome-lysosome system. HSP90 perturbation selectively inhibited VEGF-A-stimulated human endothelial cell migration in vitro. A mouse femoral artery model showed that HSP90 inhibition also blocked blood vessel repair in vivo consistent with decreased endothelial regeneration. Depletion of either HSP70 or HSP90 caused defects in blood vessel formation in a transgenic zebrafish model. We conclude that perturbation of the HSP70-HSP90 heat-shock protein axis stimulates degradation of endothelial VEGFR2 and modulates VEGF-A-stimulated intracellular signaling, endothelial cell migration, blood vessel development and repair. |
| Links |
PubMed Online version:10.1371/journal.pone.0048539 |
| Keywords |
|
| edit table |
Significance
Annotations
| Gene product | Qualifier | GO Term | Evidence Code | with/from | Aspect | Extension | Notes | Status |
|---|---|---|---|---|---|---|---|---|
|
DANRE:A8WFS0 |
involved_in |
GO:0001568: blood vessel development |
ECO:0000315: mutant phenotype evidence used in manual assertion |
ZFIN:ZDB-MRPHLNO-121213-3 |
P |
Seeded From UniProt |
complete | |
|
DANRE:B0S610 |
involved_in |
GO:0001568: blood vessel development |
ECO:0000315: mutant phenotype evidence used in manual assertion |
ZFIN:ZDB-MRPHLNO-121213-3 |
P |
Seeded From UniProt |
complete | |
|
DANRE:B7ZV46 |
involved_in |
GO:0001568: blood vessel development |
ECO:0000315: mutant phenotype evidence used in manual assertion |
ZFIN:ZDB-MRPHLNO-121213-3 |
P |
Seeded From UniProt |
complete | |
|
DANRE:HS90B |
involved_in |
GO:0001568: blood vessel development |
ECO:0000315: mutant phenotype evidence used in manual assertion |
ZFIN:ZDB-MRPHLNO-121213-4 |
P |
Seeded From UniProt |
complete | |
|
DANRE:Q8UUJ8 |
involved_in |
GO:0001568: blood vessel development |
ECO:0000315: mutant phenotype evidence used in manual assertion |
ZFIN:ZDB-MRPHLNO-121213-3 |
P |
Seeded From UniProt |
complete | |
| GO:0004716: receptor signaling protein tyrosine kinase activity |
ECO:0000314: |
F |
Figure one shows that 'HUVECs were subjected to geldanamycin (17-DMAG) treatment for indicated times, lysed and processed for immunoblotting (IB) to analyze indicated protein levels. Arrowhead indicates mature VEGFR2; TfR, transferrin receptor. (B) Quantification of mature VEGFR2 levels in control and geldanamycin-treated endothelial cells' |
complete | ||||
See also
References
See Help:References for how to manage references in GONUTS.
