Initial events of myelination involve Fyn tyrosine kinase signalling

Abstract

Myelin is the lipoprotein multimembrane that functions as an insulator preventing the flow of ion currents across the axonal membrane and facilitating the conduction of nerve impulses. It is synthesized by oligodendrocytes in the central nervous system at about the time of birth in mammals. During the initial stages of myelination, several proteins are phosphorylated on tyrosine. Among these proteins, we identified Fyn tyrosine kinase, one of the non-receptor-type tyrosine kinases of the Src family. Here we report that Fyn tyrosine kinase is activated during the initial stages of myelination and that it is associated with the large myelin-associated glycoprotein (MAG), an adhesion molecule that has been implicated in myelinogenesis. The Fyn-large MAG association requires amino-terminal domains of Fyn that include SH2 and SH3 (Src homology domains 2 and 3). Crosslinking of large MAG with antibody induces a rapid increase in the specific activity of Fyn kinase. These results indicate that Fyn participates in the initial events of myelination as a signalling molecule downstream of large MAG; indeed, we find that fyn-deficient mice exhibit impaired myelination.

Myelin associated glycoprotein cross-linking triggers its partitioning into lipid rafts, specific signaling events and cytoskeletal rearrangements in oligodendrocytes

“…Fyn is a member of the Src family of kinases and is associated with cell adhesion, migration, proliferation, differentiation, apoptosis and cytoskeletal rearrangements (Osterhout et al, 1999). Increased phosphorylation of Fyn following MAG cross-linking in double-transfected COS cells has been reported previously (Umemori et al, 1994;Umemori et al, 1999). The main site of Fyn autophosphorylation is Tyr418, which leads to activation of kinase activity.…”

“…Binding of an extracellular domain of MAG to apposing molecules on the axonal surface generates an inhibitory signal in the neuron that involves p75, RhoA and Rac1 signaling (Niederost et al, 2002;Wang et al, 2002). In addition, intracellular domains of MAG bind to microtubules (Kursula et al, 2001) and Fyn tyrosine kinase (Umemori et al, 1994;Umemori et al, 1999) in OLs.…”

Src-family tyrosine kinase fyn phosphorylates phosphatidylinositol 3-kinase enhancer-activating Akt, preventing its apoptotic cleavage and promoting cell survival

“…For example, fyn is essential for myelin development in the central nervous system (CNS) and mediates learning and memory. 13,14,28,29 Conceivably, fyn-mediated PIKE-A phosphorylation might regulate its biological functions in the brain. In summary, our data provide compelling evidence that active fyn is a physiological tyrosine kinase for PIKE-A.…”

“…8 Src kinases are activated by a variety of cell surface receptors, G-protein-coupled receptors 10 and by growth factor receptor stimulation. 11 Fyn, a critical member of src family tyrosine kinase, mediates a variety of cellular processes, including signaling via the T-cell receptor, 12 regulation of brain function 13,14 as well as adhesion-mediated signaling. 15,16 It is worth noting that src tyrosine kinases including fyn also mediate cell survival.…”

P2X7 receptors and Fyn kinase mediate ATP-induced oligodendrocyte progenitor cell migration

“…Fyn, a member of the Src family of kinases, has been reported to play a key role in regulating OPC proliferation and differentiation [41][42][43]. In primary cultured OPCs, we found that both P2X7 receptors and Fyn were expressed in OPCs (Fig.…”