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RNF121 Inhibits Angiogenic Growth Factor Signaling by Restricting Cell Surface Expression of VEGFR-2

Armin Maghsoudlou1, Rosana D Meyer1, Kobra Rezazadeh1

  • 1Department of Pathology and Laboratory Medicine, Boston University Medical Campus, Boston, MA 02118, USA.

Traffic (Copenhagen, Denmark)
|November 26, 2015
PubMed

Insights

Ring Finger Protein 121 (RNF121) regulates vascular endothelial growth factor receptor-2 (VEGFR-2) maturation in the endoplasmic reticulum. RNF121 controls VEGFR-2 cell surface levels, impacting endothelial cell proliferation and angiogenesis.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Receptor Tyrosine Kinases (RTKs) are crucial for cell signaling but their downregulation mechanisms, particularly trafficking in the ER/Golgi, remain unclear.
  • Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) is a key RTK in angiogenesis, essential for both normal and pathological processes.

Purpose of the Study:

  • To investigate the role of Ring Finger Protein 121 (RNF121) in the endoplasmic reticulum (ER) mediated maturation and trafficking of VEGFR-2.
  • To elucidate the impact of RNF121 on VEGFR-2 cell surface expression and its downstream signaling in angiogenesis.

Main Methods:

  • Utilized overexpression and shRNA-mediated knockdown of RNF121 in endothelial cells.
  • Assessed VEGFR-2 ubiquitination, maturation, and cell surface levels.
  • Examined the functional requirement of the RING Finger domain of RNF121.
  • Evaluated the effects of RNF121 on VEGF-induced endothelial cell proliferation and angiogenesis.

Main Results:

  • RNF121, an ER ubiquitin E3 ligase, recognizes and regulates VEGFR-2 maturation.
  • Overexpression of RNF121 increased VEGFR-2 ubiquitination, reduced its maturation, and decreased cell surface presence.
  • RNF121 knockdown decreased VEGFR-2 ubiquitination and increased its cell surface levels.
  • The RING Finger domain of RNF121 is essential for its regulatory activity on VEGFR-2.

Conclusions:

  • RNF121 is identified as a critical regulator of VEGFR-2 trafficking and maturation within the ER.
  • RNF121 restricts VEGFR-2 cell surface abundance, thereby inhibiting VEGF-induced endothelial cell proliferation and angiogenesis.
  • RNF121 acts as a key determinant in controlling angiogenic signaling pathways.
Keywords:
RING Finger protein 121VEGFR-2angiogenesisendoplasmic reticulum ubiquitin E3 ligasereceptor tyrosine kinaseubiquitination

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