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Development and Application of Rapamycin-regulated Tyrosine Phosphatases
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Development and Application of Rapamycin-regulated Tyrosine Phosphatases

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PEST motif serine and tyrosine phosphorylation controls vascular endothelial growth factor receptor 2 stability and

Rosana D Meyer1, Srimathi Srinivasan, Amrik J Singh

  • 1Department of Pathology, Boston University Medical Campus, 670 Albany St., Boston, MA 02118, USA.

Molecular and Cellular Biology
|March 16, 2011
PubMed

Insights

Vascular endothelial growth factor receptor 2 (VEGFR-2) degradation is controlled by its PEST domain, regulating angiogenesis. Phosphorylation at Ser1188/Ser1191 triggers ubiquitination and proteasomal degradation, while phosphorylation at Tyr1173 stabilizes VEGFR-2 via p38 MAPK.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Vascular endothelial growth factor receptor 2 (VEGFR-2) is crucial for angiogenesis, a process involving new blood vessel formation.
  • Regulation of VEGFR-2 levels is essential for controlling VEGF signaling in angiogenesis.

Purpose of the Study:

  • To elucidate the molecular mechanisms governing VEGFR-2 internalization, ubiquitination, and degradation.
  • To identify key regulatory sites and signaling pathways involved in VEGFR-2 stability and turnover.

Main Methods:

  • VEGF stimulation assays
  • Ubiquitination and degradation studies
  • Site-directed mutagenesis
  • Western blotting
  • MAPK pathway analysis

Main Results:

  • VEGF stimulation induces VEGFR-2 ubiquitination, specifically Lys 48-linked polyubiquitination, targeting it for 26S proteasomal degradation.
  • The PEST domain of VEGFR-2 is critical for its ubiquitination and degradation.
  • Phosphorylation of Ser1188/Ser1191 is required for β-Trcp1 E3 ligase recruitment and subsequent ubiquitination.
  • Phosphorylation of Tyr1173 by PKA, recruited via AKAP1/AKAP149, activates p38 MAPK, which stabilizes VEGFR-2.
  • The PEST domain acts as a dual regulator, controlling both degradation and stability pathways.

Conclusions:

  • VEGFR-2 stability and degradation are tightly regulated by a dual mechanism involving its PEST domain.
  • Phosphorylation events at distinct serine/threonine and tyrosine residues dictate VEGFR-2's fate, either promoting degradation or enhancing stability.
  • This intricate regulatory network fine-tunes VEGFR-2 signaling, impacting angiogenesis.

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