The Lymphocyte Function-Associated antigen-1 Receptor Costimulates Plasma Membrane Ras via Phospholipase D2

Nat Cell Biol. 2007 Jun;9(6):713-9. doi: 10.1038/ncb1592. Epub 2007 May 7.

Abstract

Ras activation as a consequence of antigen receptor (T-cell receptor; TCR) engagement on T lymphocytes is required for T-cell development, selection and function. Lymphocyte function-associated antigen-1 (LFA-1) mediates lymphocyte adhesion, stabilization of the immune synapse and bidirectional signalling. Using a fluorescent biosensor we found that TCR activation with or without costimulation of CD28 led to activation of Ras only on the Golgi apparatus, whereas costimulation with LFA-1 induced Ras activation on both the Golgi and the plasma membrane. Ras activation on both compartments required RasGRP1, an exchange factor regulated by calcium and diacylglycerol (DAG), but phospholipase C (PLC) activity was required only for activation on the Golgi. Engagement of LFA-1 increased DAG levels at the plasma membrane by stimulating phospholipase D (PLD). PLD2 and phosphatidic acid phosphatase (PAP) were required for Ras activation on the plasma membrane. Thus, LFA-1 acts through PLD2 to reshape the pattern of Ras activation downstream of the TCR.

Publication types

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

MeSH terms

  • Animals
  • CD28 Antigens / metabolism
  • Cell Communication / physiology
  • Cell Membrane / metabolism*
  • DNA-Binding Proteins / metabolism
  • Diglycerides / metabolism
  • Enzyme Activation / physiology
  • Golgi Apparatus / metabolism
  • Guanine Nucleotide Exchange Factors / metabolism
  • Humans
  • Jurkat Cells
  • Lymphocyte Function-Associated Antigen-1 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phospholipase D / metabolism*
  • Receptors, Antigen, T-Cell / metabolism*
  • Signal Transduction / physiology
  • T-Lymphocytes / metabolism*
  • Type C Phospholipases / metabolism
  • ras Proteins / metabolism*

Substances

  • CD28 Antigens
  • DNA-Binding Proteins
  • Diglycerides
  • Guanine Nucleotide Exchange Factors
  • Lymphocyte Function-Associated Antigen-1
  • RASGRP1 protein, human
  • Receptors, Antigen, T-Cell
  • Type C Phospholipases
  • phospholipase D2
  • Phospholipase D
  • ras Proteins