PPFIA1 drives active α5β1 integrin recycling and controls fibronectin fibrillogenesis and vascular morphogenesis

Nat Commun. 2016 Nov 23;7:13546. doi: 10.1038/ncomms13546.

Abstract

Basolateral polymerization of cellular fibronectin (FN) into a meshwork drives endothelial cell (EC) polarity and vascular remodelling. However, mechanisms coordinating α5β1 integrin-mediated extracellular FN endocytosis and exocytosis of newly synthesized FN remain elusive. Here we show that, on Rab21-elicited internalization, FN-bound/active α5β1 is recycled to the EC surface. We identify a pathway, comprising the regulators of post-Golgi carrier formation PI4KB and AP-1A, the small GTPase Rab11B, the surface tyrosine phosphatase receptor PTPRF and its adaptor PPFIA1, which we propose acts as a funnel combining FN secretion and recycling of active α5β1 integrin from the trans-Golgi network (TGN) to the EC surface, thus allowing FN fibrillogenesis. In this framework, PPFIA1 interacts with active α5β1 integrin and localizes close to EC adhesions where post-Golgi carriers are targeted. We show that PPFIA1 is required for FN polymerization-dependent vascular morphogenesis, both in vitro and in the developing zebrafish embryo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cells, Cultured
  • Embryo, Nonmammalian
  • Fibronectins / genetics
  • Fibronectins / metabolism*
  • Gene Expression Regulation / physiology*
  • Golgi Apparatus / physiology
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Integrin alpha5beta1 / genetics
  • Integrin alpha5beta1 / metabolism*
  • Neovascularization, Physiologic / physiology
  • Zebrafish

Substances

  • Adaptor Proteins, Signal Transducing
  • Fibronectins
  • Integrin alpha5beta1
  • PPFIA1 protein, human