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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.
Figure
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-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. Furthermore, anti-GPI-anchored protein antibodies co-immunoprecipitate src-family kinases, and anti-GSL antibodies co-immunoprecipitate src-family kinases and GPI-anchored proteins. 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.
Figure
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 the initiation site of the MAP kinase cascade. Protein kinase C is known to translocate from cytosol to membrane during activation. Specific association of protein kinase C alpha with GSL microdomains has been reported.

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, Ikonen E : Functional rafts in cell membranes. Nature 387, 569-572, 1997
(2) Brown, DA, London E : Functions of lipid rafts in biological membranes. Annu. Rev. Cell Dev. Biol. 14, 111-136, 1998
(3) Hakomori, S, Handa, K, Iwabuchi, K, Yamamura, S, Prinetti A : New insights in glycosphingolipid function: "glycosignaling domain," a cell surface assembly of glycosphingolipids with signal transducer molecules, involved in cell adhesion coupled with signaling. Glycobiology 8(10), pp.xi-xix , 1998
(4) Kasahara, K, Sanai, Y : Glycosphingolipid microdomains / caveolae and signal transduction. (in Japanese) Protein, Nucleic Acid and Enzyme 43(16), 2522-2530, 1998
(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
Mar.15, 1999
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