Differential Regulation of Focal Adhesion Kinase and Mitogen‐Activated Protein Kinase Tyrosine Phosphorylation During Insulin‐Like Growth Factor‐I‐Mediated Cytoskeletal Reorganization

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Abstract
In SH‐SY5Y human neuroblastoma cells, insulin‐like growth factor (IGF)‐I mediates membrane ruffling and growth cone extension. We have previously shown that IGF‐I activates the tyrosine phosphorylation of focal adhesion kinase (FAK) and extracellular signal‐regulated protein kinase (ERK) 2. In the current study, we examined which signaling pathway underlies IGF‐I‐mediated FAK phosphorylation and cytoskeletal changes and determined if an intact cytoskeleton was required for IGF‐I signaling. Treatment of SH‐SY5Y cells with cytochalasin D disrupted the actin cytoskeleton and prevented any morphological changes induced by IGF‐I. Inhibitors of phosphatidylinositol 3‐kinase (PI 3‐K) blocked IGF‐I‐mediated changes in the actin cytoskeleton as measured by membrane ruffling. In contrast, PD98059, a selective inhibitor of ERK kinase, had no effect on IGF‐I‐induced membrane ruffling. In parallel with effects on the actin cytoskeleton, cytochalasin D and PI 3‐K inhibitors blocked IGF‐I‐induced FAK tyrosine phosphorylation, whereas PD98059 had no effect. It is interesting that cytochalasin D did not block IGF‐I‐induced ERK2 tyrosine phosphorylation. Therefore, it is likely that FAK and ERK2 tyrosine phosphorylations are regulated by separate pathways during IGF‐I signaling. Our study suggests that integrity as well as dynamic motility of the actin cytoskeleton mediated by PI 3‐K is required for IGF‐I‐induced FAK tyrosine phosphorylation, but not for ERK2 activation.

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