Lipid Raft and Signal Transduction

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Lipid Raft and Signal Transduction

• Tao Chen

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Lipid Raft

• A cholesterol-enriched microdomain in cell
  membrane.
• A liquid-ordered phase dispersed in a liquid
  disordered matrix of cell membrane, which is
  thought to minimize the free energy between the
  two phases.
• Can include and exclude proteins to variable
  extents.
• Resistent to non-ionic detergents, such as Triton
  X-100 or Brij-98 at low temperatures (e.g., 4?).
• Also called DRM, DIG, DIC, GPI domain,
  Glycosphingolipid signaling domain, caveolae-like
  domain, microdomain, LDM, lipid-ordered domain,
  DIM, GEM and TIFF.

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• A Intracellular space or cytosol
• B Extracellular space or vesicle/Golgi apparatus
  lumen
• (1)Non-raft membrane (2)Lipid raft (3)Lipid raft
  associated transmembrane protein (4)Non-raft
  membrane protein
• (5)Glycosylation modifications (6)GPI-anchored
  protein (7)Cholesterol (8)Glycolipid

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Techniques to Identify Lipid Raft
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Signal Transduction

• Signal transduction refers to any process by
  which a cell converts one kind of signal or
  stimulus into another.
• Ligand bind to receptor Receptor change its
  conformation Enzyme bind to receptor
  Enzyme is activated
• Red chemical messenger
• Yellow transmembrane protein
• Purple cell membrane
• Green enzyme

http//www.youtube.com/watch?vtMMrTRnFdI4
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How receptors signal through lipid rafts?

• Through the connection of raft proteins and
  interacting proteins to form a complex, resulting
  in the activation of signalling cascade.

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(1) Single Rafts Model

• (a) Receptors associated at steady
• state with lipid rafts could be activated
  through ligand binding
• (b) Individual receptors with weak raft affinity
  could oligomerize on ligand binding, and this
  would lead to an increased residency time in
  rafts.

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(2) Clustered Rafts Model

• Activated receptors could recruit
• cross linking proteins that bind to proteins in
  other
• rafts, and this would result in raft coalescence.

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• Clustering of lipid raft can occur both
  extracellularly, within the membrane, and in the
  cytosol. It can also occur through GPI anchored
  proteins, either as a primary or co-stimulatory
  response.
• These two models are not mutually exclusive.

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T-Cell Antigen Receptor Signalling

• The T cell receptor or TCR is a heterodimer
  consisting of an alpha and beta chain.
• Alpha, beta heterdimer associate with CD3 complex
  and ? homodimer which contain cytoplasmic ITAM
  motifs (immune receptor tyrosine-based activation
  motifs).

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• Ligand-induced receptor dimerization of TCR/CD3
• Phosphorylation of the receptors ITAMs by
  Src-family protein tyrosine kinases

• Phosphorylated ITAMs act as a membrane docking
  site for ZAP-70
• ZAP-70 activate other proteins such as LAT, a
  raft-associated adaptor, through cross linking,
  LAT can recruit other proteins into the raft and
  further amplify the signal.
• Cytosolic kinase Csk bind to raft-associated
  protein CBP and then inactivate the Src-family
  kinases through phosphorylation

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Open Issues

• Raft composition
• Whether more than one kind of raft exists on the
  cell surface of different cell types.
• Understanding the nature of individual rafts.
• How single rafts are crosslinked to form
  clustered rafts during signal transduction.

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References

• Kai Simons and Derek Toomre, Lipid Rafts and
  Signal Transduction, Nature Reviews-Molecular
  Cell Biology, 2000, 1, 31-41
• Brown D A, London E, Functions of Lipid Rafts in
  Biological Membranes, Annu. Rev. Cell. Dev. Biol,
  1998, 14, 111-136
• Schroeder R, London E, Brown D, Interactions
  between saturated acyl chains confer detergent
  resistent on lipids and glycosylphosphatidylinosit
  ol(GPI)-anchored proteins GPI-anchored proteins
  in liposomes and cells show similar behavior,
  Proc. Natl Acad. Sci. USA, 1994, 91, 12130-12134
• Zhang W, Trible R P, Samelson L E, LAT
  palmitoylation its essential role in membrane
  microdomain targeting and tyrosine
  phosphorylation during T-cell activation,
  immunity, 1998, 9, 239-246

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