Low Density Lipoprotein Receptor-related Protein (LRP1) Regulates Rac1 and RhoA Reciprocally to Control Schwann Cell Adhesion and Migration

Abstract

LDL receptor-related protein (LRP1) is expressed by Schwann cells in vivo mainly after injury to the peripheral nervous system (PNS). Schwann cells in primary culture, which provide a model of Schwann cells in the injured PNS, also express abundant LRP1. Herein, we show that LRP1 gene-silencing or treatment with receptor-associated protein (RAP) promotes Schwann cell adhesion and inhibits cell migration on fibronectin. LRP1 genesilencing also resulted in the formation of prominent focal adhesions and actin stress fibers. These changes, which were induced by loss of LRP1 expression or activity, were explained mechanistically by an increase in activated RhoA, coupled with a decrease in activated Rac1. Known LRP1 ligands, including matrix metalloprotease-9, tissue-type plasminogen activator, and In the mature, uninjured peripheral nervous system (PNS), 2 Schwann cells are typically immobile, providing trophic support and in some cases, ensheathing and myelinating axons (1). PNS injury triggers Schwann cell dedifferentiation, allowing these cells to survive, detach from axonal connections, proliferate, and migrate (2). Dedifferentiation is essential for PNS regeneration (3). Many exogenous factors have been reported to stimulate migration of dedifferentiated Schwann cells, including neurotrophin-3 (NT-3), neuregulin-1, and insulinlike growth factor-I (4 -6). These factors promote migration, at least in part, by activating the Rho family GTPases, Rac1 and Cdc42. Rac1 promotes dynamic actin remodeling, lamellipodia formation and random cell migration (7,8). Cdc42 controls cell polarity and allows for directionally persistent cell migration (9). In Schwann cells, the ability of Rac1 to promote cell migration may be counteracted by high levels of activated RhoA and its downstream effector, Rho kinase (10). RhoA activation may be inhibited by Rac1 and Rac1 activation may be inhibited downstream of Rho kinase, allowing for orchestration of these GTPases in the control of cell morphology and migration (11)(12)(13)(14). In development, Schwann cell Rac1 facilitates radial axonal sorting and myelination (15).Gene products that control transformation of the Schwann cell phenotype in PNS injury remain incompletely characterized. We recently identified low density lipoprotein receptorrelated protein (LRP1) as a receptor expressed by Schwann cells mainly after PNS injury (16). LRP1 is a 600-kDa type I transmembrane protein in the LDL receptor gene family, originally characterized as an endocytic receptor, but currently recognized also for its role in cell signaling (17, 18). Diverse proteins implicated in PNS injury, including matrix metalloprotease-9 (MMP-9), tissue-type plasminogen activator (tPA), and activated ␣ 2 -macroglobulin (␣ 2 M) bind to LRP1 and activate Akt and ERK/MAP kinase in Schwann cells in vitro and in the injured . By its effect on cell signaling, LRP1 promotes Schwann cell survival and migration (16,19).Although the increase in Schwann cell migration, observed when cells are treated with MMP-9, has been attr...

Novel Role for p21-activated Kinase 2 in Thrombin-induced Monocyte Migration

“…As Gab1 via recruiting RhoGEFs, such as p115 RhoGEF, mediates Rho GTPases activation, there is the possibility that Gab1-induced cell-cell contacts downstream to c-Met may be mediated by Rac1 or RhoA. Some reports showed that both Rac1 and RhoA reciprocate in the stimulus-induced modulation of cell migration and invasion (38). However, in the present study, we showed that Rac1 and RhoA cooperate in the mediation of thrombin-induced F-actin cytoskeleton formation and migration.…”

“…4, E and F). Some reports indicated that Rac1 and RhoA reciprocate in the mediation of cellular responses, such as cell migration (38). Because down-regulation of either p115 RhoGEF or Gab1 inhibited thrombin-induced activation of both Rac1 and RhoA, we were intrigued to find whether there is any interaction between these RhoGTPases.…”

miR-9 inhibits Schwann cell migration by targeting CTHRC1 following sciatic nerve injury

“…Many growth factors, including neurotrophin-3, neuregulin-1 and insulin-like growth factor-1, stimulate migration of dedifferentiated Schwann cells (Cheng et al, 2000;Mantuano et al, 2010;Yamauchi et al, 2005). These factors promote cell migration, at least in part, by activating the Rho family GTPases.…”

Low-density Lipoprotein Receptor-related Protein 1 (LRP1)-dependent Cell Signaling Promotes Axonal Regeneration

“…Recent reports have suggested a potential role for LRP1 in neural function and growth. LRP1 acts as a prosurvival and migratory receptor in Schwann cells after peripheral nerve injury (11,19), transduces a signal for phagocytosis of degraded myelin in experimental models of multiple sclerosis (20), and modulates processing of the amyloid precursor protein (20 -22, 3). Recently, LRP1 agonists were also reported to induce transactivation of TrkA in a Src family kinase (SFK) 3 dependent manner, promoting neurite outgrowth from PC12 cells (23).…”