In multiple sclerosis (MS), oligodendrocytes in lesions are lost, leaving damaged tissue virtually devoid of these myelin-producing cells. Our group has recently demonstrated enhanced expression of insulin-like growth factor (IGF) binding protein-1 (IGFBP-1) in oligodendrocytes (CNPase(+)) localized adjacent to MS lesions. In the present study, we demonstrate IGF-1-independent actions of IGFBP-1 on OLN-93 oligodendroglial cells, including activation of kinases ERK1/2, focal adhesion kinase and p21-activated kinase as well as small monomeric GTPases Rac and Ral. Activation of these intracellular signaling components was inhibited by GRGDS peptide, indicating signaling through integrin receptors. While both IGF-1 and IGFBP-1 demonstrated rapid induction of actin polymerization, IGFBP-1 proved to be a more potent inducer of migration than IGF-1, inducing a threefold increased migration rate. Furthermore, through integrin receptor signaling IGFBP-1 induced rapid transient translocalization of intracellular Rac toward punctuated structures followed by translocation of Rac to the plasma membrane. Our results suggest that up-regulation of IGFBP-1 in oligodendrocytes in MS may serve two functions: (i) regulate IGF-1 actions, (ii) exert IGF-independent effects through its RGD sequence.