2 MITOGENIC REGIONS OF MYELIN BASIC-PROTEIN INTERACT WITH DIFFERENT RECEPTORS TO INDUCE SCHWANN-CELL PROLIFERATION IN A CAMP-DEPENDENT PROCESS

Previous studies have shown that myelin basic protein (MBP) is mitogen ic for Schwann cells (SCs) in the presence of elevated intracellular c AMP, Two mitogenic regions of MBP have been identified: one mitogenic region within the first 44 residues of the amino-terminus (1-44) and t he other mitogenic region within the terminal 15 residues of the carbo xyl end of the molecule (152-167), Unlike the mitogenic effect of a my elin enriched fraction (MEF), the mitogenic effect of MBP was not redu ced by the addition of the lysosomal inhibitor, ammonium chloride, The se data indicate that MBP causes SC proliferation by direct interactio n of MBP with a surface receptor. Using Scatchard analysis of the bind ing of MBP to SCs, we report that treatment with forskolin does not ca use the upregulation of receptors for MBP, Moreover, MBP blocks the cr oss-linking of I-125-bFGF with two fibroblast growth factor (FGF) rece ptors having apparent molecular weights of 140 kDa and 120 kDa, respec tively, Since neither TGF-beta nor PDGF-BB displaced cell surface boun d I-125-MBP, we conclude that MBP binds to the FGF receptor rather tha n other growth factor receptors. Furthermore, only MBP(1-44) interacte d with ganglioside GM1, whereas MBP(152-167) did not interact with thi s ganglioside, These results are consistent with the view that ganglio side GM1 mediates the mitogenic effects of MBP(1-44), while the FGF re ceptor mediates the mitogenic effect of MBP(152-167). Intracellular cA MP of SCs was transiently increased after the addition of macrophage c onditioned medium, suggesting that macrophages may produce factors in vivo which can transiently elevate intracellular cAMP levels, allowing a wave of SC proliferation in response to MBP-related mitogens. (C) 1 995 Wiley-Liss, Inc.