Skip NavigationSkip to Content

Vav1 is Essential for HIF-1a Activation via a Lysosomal VEGFR1-Mediated Degradation Mechanism in Endothelial Cells

  1. Author:
    Hong,Jaewoo [ORCID]
    Min,Yongfen
    Wuest, Todd
    Lin,Charles
  2. Author Address

    Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21704, USA.,
    1. Year: 2020
    2. Date: JUN
    3. Epub Date: 2020 05 27
  1. Journal: Cancers
    1. 12
    2. 6
    3. Pages: E1374
  2. Type of Article: Article
  3. Article Number: 1374
  4. ISSN: 2072-6694
  1. Abstract:

    The vascular response to hypoxia and ischemia is essential for maintaining homeostasis during stressful conditions and is particularly critical for vital organs such as the heart. Hypoxia-inducible factor-1 (HIF-1) is a central regulator of the response to hypoxia by activating transcription of numerous target genes, including vascular endothelial growth factor (VEGF). Here we identify the guanine nucleotide exchange factor (GEF) Vav1, a regulator of the small Rho-GTPase and cell signaling in endothelial cells, as a key vascular regulator of hypoxia. We show that Vav1 is present in the vascular endothelium and is essential for HIF-1 activation under hypoxia. So, we hypothesized that Vav1 could be a key regulator of HIF-1 signaling. In our findings, Vav1 regulates HIF-1a stabilization through the p38/Siah2/PHD3 pathway. In normoxia, Vav1 binds to vascular endothelial growth factor receptor 1 (VEGFR1), which directs Vav1 to lysosomes for degradation. In contrast, hypoxia upregulates Vav1 protein levels by inhibiting lysosomal degradation, which is analogous to HIF-1a regulation by hypoxia: both proteins are constitutively produced and degraded in normoxia allowing for a rapid response when stress occurs. Consequently, hypoxia rapidly stabilizes Vav1, which is required for HIF-1a accumulation. This shows that Vav1 is the key mediator controlling the stabilization of HIF1a in hypoxic conditions. With this finding, we report a novel pathway to stabilize HIF-1, which shows a possible reason why clinical trials targeting HIF-1 has not been effective. Targeting Vav1 can be the new approach to overcome hypoxic tumors.

    See More

External Sources

  1. DOI: 10.3390/cancers12061374
  2. PMID: 32471123
  3. WOS: 000549318500001
  4. PII : cancers12061374

Library Notes

  1. Fiscal Year: FY2019-2020
NCI at Frederick

You are leaving a government website.

This external link provides additional information that is consistent with the intended purpose of this site. The government cannot attest to the accuracy of a non-federal site.

Linking to a non-federal site does not constitute an endorsement by this institution or any of its employees of the sponsors or the information and products presented on the site. You will be subject to the destination site's privacy policy when you follow the link.

ContinueCancel