MAP4K4 Regulates integrin-FERM Binding to Control Endothelial Cell Motility

Nature. 2015 Mar 26;519(7544):425-30. doi: 10.1038/nature14323. Epub 2015 Mar 18.

Abstract

Cell migration is a stepwise process that coordinates multiple molecular machineries. Using in vitro angiogenesis screens with short interfering RNA and chemical inhibitors, we define here a MAP4K4-moesin-talin-β1-integrin molecular pathway that promotes efficient plasma membrane retraction during endothelial cell migration. Loss of MAP4K4 decreased membrane dynamics, slowed endothelial cell migration, and impaired angiogenesis in vitro and in vivo. In migrating endothelial cells, MAP4K4 phosphorylates moesin in retracting membranes at sites of focal adhesion disassembly. Epistasis analyses indicated that moesin functions downstream of MAP4K4 to inactivate integrin by competing with talin for binding to β1-integrin intracellular domain. Consequently, loss of moesin (encoded by the MSN gene) or MAP4K4 reduced adhesion disassembly rate in endothelial cells. Additionally, α5β1-integrin blockade reversed the membrane retraction defects associated with loss of Map4k4 in vitro and in vivo. Our study uncovers a novel aspect of endothelial cell migration. Finally, loss of MAP4K4 function suppressed pathological angiogenesis in disease models, identifying MAP4K4 as a potential therapeutic target.

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cell Movement*
  • Cell Shape / drug effects
  • Endothelial Cells / cytology*
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Epistasis, Genetic
  • Focal Adhesions / metabolism
  • Humans
  • Integrin alpha1 / drug effects
  • Integrin alpha1 / metabolism
  • Integrin beta1 / chemistry
  • Integrin beta1 / drug effects
  • Integrin beta1 / metabolism
  • Integrins / drug effects
  • Integrins / metabolism*
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • Intracellular Signaling Peptides and Proteins / deficiency
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Mice
  • Microfilament Proteins / deficiency
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism
  • Neovascularization, Pathologic
  • Phosphorylation
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Talin / chemistry
  • Talin / metabolism

Substances

  • Integrin alpha1
  • Integrin beta1
  • Integrins
  • Intracellular Signaling Peptides and Proteins
  • Microfilament Proteins
  • Talin
  • moesin
  • MAP4K4 protein, human
  • Protein-Serine-Threonine Kinases