Lipid Raft and Signal Lipid Raft and Signal TransductionTransduction

Tao ChenTao Chen

Lipid RaftLipid Raft• A cholesterol-enriched microdomain in cell membran

e. • A liquid-ordered phase dispersed in a liquid disordere

d 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-10

0 or Brij-98 at low temperatures (e.g., 4℃).• Also called DRM, DIG, DIC, GPI domain, Glycosphingoli

pid signaling domain, caveolae-like domain, microdomain, LDM, lipid-ordered domain, DIM, GEM and TIFF.

A Intracellular space or cytosol B Extracellular space or vesicle/Golgi apparatus lume

n (1)Non-raft membrane (2)Lipid raft (3)Lipid raft associat

ed transmembrane protein (4)Non-raft membrane protein

(5)Glycosylation modifications (6)GPI-anchored protein (7)Cholesterol (8)Glycolipid

Techniques to Identify Lipid Techniques to Identify Lipid Raft:Raft:

Signal TransductionSignal Transduction• Signal transduction refers to any process by which a cel

l converts one kind of signal or stimulus into another.• Ligand bind to receptor Receptor change its conform

ation Enzyme bind to receptor Enzyme is activated

Red: chemical messengerYellow: transmembrane protein Purple: cell membraneGreen: enzyme

http://www.youtube.com/watch?v=tMMrTRnFdI4

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

(a) Receptors associated at steady state with lipid rafts could be activated through ligand bin

ding(b) Individual receptors with weak raft affinity could oligome

rize on ligand binding, and this would lead to an increased residency time in rafts.

(1) Single Rafts Model(1) Single Rafts Model

Activated receptors could recruitcross linking proteins that bind to proteins in otherrafts, and this would result in raft coalescence.

(2) Clustered Rafts Model(2) Clustered Rafts Model

• 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.

T-Cell Antigen Receptor SignallT-Cell Antigen Receptor Signallinging

• The T cell receptor or TCR is a heterodimer consisting of an alpha and beta chain.

• Alpha, beta heterdimer associate with CD3 complex and ζ homodimer which contain cytoplasmic ITAM motifs (immune receptor tyrosine-based activation motifs).

• 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

• Ligand-induced receptor dimerization of TCR/CD3

• Phosphorylation of the receptor’s ITAMs by Src-family protein tyrosine kinases

Open Issues:Open Issues:• Raft composition • Whether more than one kind of raft exists on the cell s

urface of different cell types.• Understanding the nature of individual rafts.• How single rafts are crosslinked to form clustered raft

s during signal transduction.

ReferencesReferences• Kai Simons and Derek Toomre, Lipid Rafts and Signal Tran

sduction, 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 glycosylphosphatidylinositol(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