YAP/TAZ-CDC42 Signaling Regulates Vascular Tip Cell Migration

Proc Natl Acad Sci U S A. 2017 Oct 10;114(41):10918-10923. doi: 10.1073/pnas.1704030114. Epub 2017 Sep 25.

Abstract

Angiogenesis and vascular remodeling are essential for the establishment of vascular networks during organogenesis. Here we show that the Hippo signaling pathway effectors YAP and TAZ are required, in a gene dosage-dependent manner, for the proliferation and migration of vascular endothelial cells (ECs) during retinal angiogenesis. Intriguingly, nuclear translocation of YAP and TAZ induced by Lats1/2-deletion blocked endothelial migration and phenocopied Yap/Taz-deficient mutants. Furthermore, overexpression of a cytoplasmic form of YAP (YAPS127D) partially rescued the migration defects caused by loss of YAP and TAZ function. Finally, we found that cytoplasmic YAP positively regulated the activity of the small GTPase CDC42, deletion of which caused severe defects in endothelial migration. These findings uncover a previously unrecognized role of cytoplasmic YAP/TAZ in promoting cell migration by activating CDC42 and provide insight into how Hippo signaling in ECs regulates angiogenesis.

Keywords: CDC42; Hippo signaling; angiogenesis; cell migration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Adaptor Proteins, Signal Transducing / physiology*
  • Animals
  • Cell Cycle Proteins
  • Cell Movement*
  • Cell Proliferation
  • Endothelium, Vascular / cytology*
  • Endothelium, Vascular / physiology
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Mice
  • Mice, Knockout
  • Neovascularization, Physiologic*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Phosphoproteins / physiology*
  • Signal Transduction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*
  • cdc42 GTP-Binding Protein / physiology*

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Phosphoproteins
  • TAZ protein, human
  • Taz protein, mouse
  • Transcription Factors
  • YAP1 (Yes-associated) protein, human
  • Yap protein, mouse
  • cdc42 GTP-Binding Protein