Epithelial cell extrusion requires the sphingosine-1-phosphate receptor 2 pathway

J Cell Biol. 2011 May 16;193(4):667-76. doi: 10.1083/jcb.201010075. Epub 2011 May 9.

Abstract

To maintain an intact barrier, epithelia eliminate dying cells by extrusion. During extrusion, a cell destined for apoptosis signals its neighboring cells to form and contract a ring of actin and myosin, which squeezes the dying cell out of the epithelium. Here, we demonstrate that the signal produced by dying cells to initiate this process is sphingosine-1-phosphate (S1P). Decreasing S1P synthesis by inhibiting sphingosine kinase activity or by blocking extracellular S1P access to its receptor prevented apoptotic cell extrusion. Extracellular S1P activates extrusion by binding the S1P(2) receptor in the cells neighboring a dying cell, as S1P(2) knockdown in these cells or its loss in a zebrafish mutant disrupted cell extrusion. Because live cells can also be extruded, we predict that this S1P pathway may also be important for driving delamination of stem cells during differentiation or invasion of cancer cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Video-Audio Media

MeSH terms

  • Actomyosin / metabolism
  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Apoptosis*
  • Cell Line
  • Dogs
  • Enzyme Inhibitors / pharmacology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Gene Knockdown Techniques
  • Lysophospholipids / metabolism*
  • Mutation
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • RNA Interference
  • Receptors, Lysosphingolipid / antagonists & inhibitors
  • Receptors, Lysosphingolipid / genetics
  • Receptors, Lysosphingolipid / metabolism*
  • Signal Transduction* / drug effects
  • Sphingosine / analogs & derivatives*
  • Sphingosine / metabolism
  • Zebrafish / embryology
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism*

Substances

  • Antibodies, Monoclonal
  • Enzyme Inhibitors
  • Lysophospholipids
  • Receptors, Lysosphingolipid
  • Zebrafish Proteins
  • sphingosine 1-phosphate
  • Actomyosin
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Sphingosine