Glycolipids and Signal Transduction

 Glycosphingolipids (GSLs) have been shown to be modulators of signal transduction by Hakomori et al. Recent studies show dynamic clustering of GSLs and cholesterol to form microdomains within the lipid bilayer and association of a variety of signaling molecules with this domain. GSLs are relatively rich in saturated fatty acyl chains, which allow tight packing and confer high melting temperature. On the other hand, phospholipids are relatively rich in cis-unsaturated fatty acyl chains (kinked structure), which prevent tight packing and confer low melting temperature. GSL microdomains may exist as phase-separated domains in the membrane. Figure 1 shows a hypothetical model. GSL microdomains are also referred to as rafts.
GPI-anchored proteins and acylated proteins like src-family tyrosine kinases and trimeric G proteins are known to associate with GSL microdomains. GPI-anchored proteins generally have saturated acyl chains, which are likely to insert preferentially into GSL microdomains. Src-family kinases are modified by saturated-chain lipids: palmitoylation and myristoylation, which are likely to insert preferentially into GSL microdomains.

Antibody(or ligand)-mediated crosslinking of GPI-anchored proteins induces activation of src-family kinases and transient increase in tyrosine phosphorylation of several substrates (Fig.2a). Antibody-mediated crosslinking of GSLs also induces activation of src-family kinases and transient increase in tyrosine phosphorylation (Fig.2b). This shows that antibody-mediated crosslinking of GSLs can mimic GPI-anchored protein signaling. Anti-GPI-anchored protein antibodies co-immunoprecipitate src-family kinases, and anti-GSL antibodies co-immunoprecipitate src-family kinases and GPI-anchored proteins. Furthermore, enzymatic removal of the carbohydrate moiety from cell-surface GSLs impairs activation of the src-family kinase by antibody-mediated crosslinking of GPI-anchored protein. These observations suggest that GSLs are involved in GPI-anchored protein signaling. Although there is some discussion as to whether GPI-anchored proteins associate with GSL microdomains at steady state, it is thought that antibody-mediated crosslinking of GPI-anchored proteins induces translocation to GSL microdomains or stabilizes association with GSL microdomains.
GSL microdomains are involved in signaling by immunoreceptors and growth factor receptors. Efficient T-cell activation requires one signal from a T-cell antigen receptor and a second signal from the costimulatory molecule. The costimulation leads to the recruitment of GSL microdomains to the site of cell-cell contact between the T cell and antigen-presenting cell. The concentration of src-family kinases and downstream molecules, and exclusion of tyrosine phosphatase CD45 allow strong and sustained tyrosine phosphorylation of several substrates. Furthermore, EGF receptor and Ras are present in GSL microdomains and EGF treatment induces translocation of Raf-1 as MAPKK kinase from cytosol to GSL microdomains. This suggests that GSL microdomains may be initiation site of the MAP kinase cascade.

The general function of GSL microdomains in signal transduction may be to concentrate receptors and effectors on both sides of the membrane, thus speeding up binding during signaling and preventing inappropriate crosstalk between pathways.
Kohji Kasahara (Tokyo Metropolitan Institute of Medical Science)
References(1)Simons K, Toomre D : Lipid rafts and signal transduction. Nature Rev. Mol.Cell Biol. 1, 31-39, 2000
(2)Kasahara K, Sanai Y : Functional roles of glycosphingolipids in signal transduction via lipid rafts. Glycoconj. J. 17 (3-4), 153-162, 2000
(3) Kasahara, K, Sanai, Y : Glycosphingolipid microdomains / caveolae and signal transduction. (in Japanese) Protein, Nucleic Acid and Enzyme 43(16), 2522-2530, 1998
(4)Kasahara K, Watanabe K, Takeuchi K, Kaneko H, Oohira A, Yamamoto T, Sanai Y : Involvement of gangliosides in glycosylphosphatidylinositol-anchored neuronal cell adhesion molecule TAG-1 signaling in lipid rafts. J Biol Chem 275
(44), 34701-34709, 2000
(5) Kasahara, K, Watanabe, Y, Yamamoto, T, Sanai , Y : Association of src family tyrosine kinase Lyn with ganglioside GD3 in rat brain. Possible regulation of Lyn by glycosphingolipid in caveolae-like domains. J. Biol. Chem. 272(47), 29947-29953, 1997
Revised; Apr. 15, 2001

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