Compartmentation of Fyn kinase with glycosylphosphatidylinositol-anchored molecules in oligodendrocytes facilitates kinase activation during myelination

In many cell types, glycosylphosphatidylinositol (GPI)-anchored proteins ar e sequestered in detergent-resistant membrane rafts. These are plasma membr ane microdomains enriched in glycosphingolipids and cholesterol and are sug gested to be platforms for cell signaling. Concomitant with the synthesis o f myelin glycosphingolipids, maturing oligodendrocytes progressively associ ate GPI-anchored proteins, including the adhesion molecules NCAM 120 and F3 , in rafts. Here we show that these microdomains include Fyn and Lyn kinase s. Both kinases are maximally active in myelin prepared from young animals, correlating with early stages of myelination. In the rafts, Fyn kinase is tightly associated with NCAM 120 and F3. In contrast, in oligodendrocyte pr ogenitor cells lacking rafts or in raft-free membrane domains of more matur e cells, F3 does not associate with Fyn. The addition of anti-F3 antibodies to oligodendrocytes results in stimulation of Fyn kinase specifically in r afts. Compartmentation of oligodendrocyte GPI-anchored proteins in rafts is thus a prerequisite for association with Fyn, permitting kinase activation . Interaction of oligodendrocyte F3 with axonal ligands such as L1 and ensu ing kinase activation may play a crucial role in initiating myelination.