The phosphatidylserine receptor TIM-4 does not mediate direct signaling

Curr Biol. 2009 Feb 24;19(4):346-51. doi: 10.1016/j.cub.2009.01.042. Epub 2009 Feb 12.

Abstract

Engulfment of apoptotic cells is an active process coordinated by receptors on phagocytes and ligands on apoptotic cells [1]. Phosphatidylserine (PtdSer) is a key ligand on apoptotic cells, and recently three PtdSer recognition receptors have been identified, namely, TIM-4, BAI1, and Stabilin-2 [1-6]. Whereas BAI1 is dependent on the ELMO1/Dock180/Rac signaling module, and Stablilin-2 appears to use the intracellular adaptor GULP [2, 3, 7], little is known about how TIM-4 transduces signals downstream of PtdSer recognition [8]. To test the role of known engulfment signaling pathways in TIM-4-mediated engulfment, we used a combination of dominant-negative mutants, knockdown of specific signaling proteins, and knockout cell lines. TIM-4 appears to be largely independent of the two known engulfment signaling pathways [7, 9-17], yet the TIM-4-mediated uptake is inhibited by cytoskeleton disrupting drugs. Remarkably, a version of TIM-4 lacking its cytoplasmic tail promoted corpse uptake via PtdSer recognition. Moreover, replacement of the transmembrane region of TIM-4 with a glycophosphatidylinositol anchor still promoted engulfment comparable to wild-type TIM-4. Thus, the transmembrane region and cytoplasmic tail of TIM-4 are dispensable for apoptotic cell engulfment, and we propose that TIM-4 is a PtdSer tethering receptor without any direct signaling of its own.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Angiogenic Proteins / genetics
  • Angiogenic Proteins / metabolism
  • Animals
  • Cell Line
  • Cytoskeleton / metabolism
  • Endocytosis / physiology
  • Humans
  • Macrophages / cytology
  • Macrophages / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Myosin Type II / metabolism
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Receptors, G-Protein-Coupled
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction / physiology*

Substances

  • ADGRB1 protein, human
  • Adaptor Proteins, Signal Transducing
  • Angiogenic Proteins
  • ELMO1 protein, human
  • Membrane Proteins
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • Recombinant Fusion Proteins
  • TIMD4 protein, human
  • phosphatidylserine receptor
  • Myosin Type II