The extracellular matrix (ECM) protein laminin (LN), has been implicated as an important component of neurite regulation in vivo. In SH-SY5Y human neuroblastoma cells, laminin induces rapid neurite outgrowth by binding to the alpha1/Beta1 integrin. In platelets, integrin ligand binding stimulates c-Src association with the actin cytoskeleton. Interestingly, c-Src has been implicated as a factor in the regulation of neurite outgrowth in SH-SY5Y and other cells in vitro and in vivo. Based on this background, we have developed the following hypothesis to describe LN- induced neurite outgrowth in SH-SY5Y cells: LN binds to the alpha/Beta1 integrin on SH-SY5Y cells, causing enhanced association of c-Src and/or other Src family kinases with the actin cytoskeleton, which then directs the structural changes necessary for neurite formation and growth cone guidance. The first specific aim of the proposed research will examine the association of Src family kinases and tyrosine phosphorylation in the actin cytoskeleton during LN-induced neurite growth. The second specific aim will assess the effect of overexpression of c-src and v-src on LN- stimulated neurite growth and signal transduction. These studies should help clarify the role of c-Src in ECM-regulated neurite growth. The findings are of importance for understanding the biochemical mechanisms involved in axonal pathfinding during development and have applications for treatment of spinal cord and other nervous tissue injuries, as well as for clarifying mechanisms of metastasis and invasion by neuroblastomas.
| Leventhal, P S; Shelden, E A; Kim, B et al. (1997) Tyrosine phosphorylation of paxillin and focal adhesion kinase during insulin-like growth factor-I-stimulated lamellipodial advance. J Biol Chem 272:5214-8 |
| Kim, B; Leventhal, P S; Saltiel, A R et al. (1997) Insulin-like growth factor-I-mediated neurite outgrowth in vitro requires mitogen-activated protein kinase activation. J Biol Chem 272:21268-73 |
| Feldman, E L; Sullivan, K A; Kim, B et al. (1997) Insulin-like growth factors regulate neuronal differentiation and survival. Neurobiol Dis 4:201-14 |
| Leventhal, P S; Feldman, E L (1996) The tyrosine kinase inhibitor methyl 2,5-dihydroxycinnimate disrupts changes in the actin cytoskeleton required for neurite formation. Brain Res Mol Brain Res 43:338-40 |
| Leventhal, P S; Feldman, E L (1996) Tyrosine phosphorylation and enhanced expression of paxillin during neuronal differentiation in vitro. J Biol Chem 271:5957-60 |
