Moesin and merlin regulate urokinase receptor-dependent endothelial cell migration, adhesion and angiogenesis

Int J Biochem Cell Biol. 2017 Jul:88:14-22. doi: 10.1016/j.biocel.2017.04.012. Epub 2017 May 1.

Abstract

The glycosyl-phosphatidyl-inositol (GPI)-anchored urokinase receptor (uPAR) has no intracellular domain, but nevertheless initiates signalling through proximal interactions with other membrane receptors including integrins. The relationships between uPAR and ezrin/radixin/moesin (ERM) proteins, moesin and merlin have never been explored. Moesin and merlin are versatile membrane-actin links and regulators of receptors signalling, respectively. We show that uPAR controls moesin and merlin, which propagate uPAR-initiated signals and modulate integrin functions, thereby regulating uPAR activity. uPAR rapidly de-phosphorylates moesin and phosphorylates merlin inactivating both proteins, and enhancing cell migration and angiogenesis. Moesin behaves as a molecular switch turning either on or off uPAR signalling through cycles of de-activation/activation, or sustained activation, respectively. Furthermore, moesin is at the crossroads of uPAR-initiated outside-in and inside-out signalling promoting integrin-dependent cell adhesion suggesting that uPAR also activates integrins distally through moesin. Knocking down merlin expression enhanced cell migration and adhesion through different regulation of fibronectin- and vitronectin-binding integrins.

Keywords: Angiogenesis; Cell adhesion; Cell migration; Merlin; Moesin; Urokinase receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Adhesion*
  • Chemotaxis*
  • Endothelial Cells / cytology*
  • Endothelial Cells / metabolism
  • Humans
  • Microfilament Proteins / metabolism*
  • Neovascularization, Physiologic*
  • Neurofibromin 2 / metabolism*
  • Receptors, Urokinase Plasminogen Activator / metabolism*

Substances

  • Microfilament Proteins
  • Neurofibromin 2
  • Receptors, Urokinase Plasminogen Activator
  • moesin