Rac1 and RhoA are regulated reciprocally downstream of low density lipoprotein receptor-related protein (LRP1) to control Schwann cell adhesion and migration

Schwann cells in the sciatic nerve express high levels of low density lipoprotein receptor-related protein (LRP1) only after undergoing phenotypic transformation in nerve injury. Schwann cells in culture also express abundant LRP1, providing a model of Schwann cells in the injured nerve. In this study, we show that LRP1 gene-silencing or treatment of Schwann cells with the LRP1 antagonist, receptor-associated protein (RAP), promotes cell adhesion and substantially inhibits cell migration on fibronectin-coated surfaces. When allowed to adhere to fibronectin, LRP1 gene-silenced cells form well-defined focal adhesions and bundle f-actin into prominent stress fibers more rapidly than control cells. These changes reflect a substantially increased level of activated RhoA and decreased activation of Rac1 in Schwann cells in which LRP1 is absent or neutralized. LRP1 ligands, including matrix metalloprotease-9, tissue-type plasminogen activator and α2-macro-globulin activated Rac1 in control Schwann cells. A pharmacologic inhibitor of Rac1 activation promoted adhesion of control Schwann cells whereas Rho kinase inhibitor promoted migration and inhibited adhesion of LRP1 gene-silenced cells. These results define LRP1 as a receptor that controls Schwann cell adhesion and migration by its effects on the activity of small Rho family GTPases. LRP1 expression transforms the Schwann cell phenotype from immobile to migratory