A Rac switch regulates random versus directionally persistent cell migration

Abstract

Directional migration moves cells rapidly between points, whereas random migration allows cells to explore their local environments. We describe a Rac1 mechanism for determining whether cell patterns of migration are intrinsically random or directionally persistent. Rac activity promoted the formation of peripheral lamellae that mediated random migration. Decreasing Rac activity suppressed peripheral lamellae and switched the cell migration patterns of fibroblasts and epithelial cells from random to directionally persistent. In three-dimensional rather than traditional two-dimensional cell culture, cells had a lower level of Rac activity that was associated with rapid, directional migration. In contrast to the directed migration of chemotaxis, this intrinsic directional persistence of migration was not mediated by phosphatidylinositol 3′-kinase lipid signaling. Total Rac1 activity can therefore provide a regulatory switch between patterns of cell migration by a mechanism distinct from chemotaxis.

Nuclear transport receptor karyopherin-α2 promotes malignant breast cancer phenotypes in vitro

“…Cell migration was significantly increased in malignant MCF7 tumor cells, compared with the benign MCF10A breast cells. Forced KPNA2 overexpression led to a remarkable increase of cell migration both in the benign MCF10A/KPNA2 and malignant MCF7/KPNA2 clones, and involved enhanced RAC-1 and p65 gene expression-two factors being relevant for cell migration (Karin et al, 2002;Pankov et al, 2005). After KPNA2 transfection, MCF10A featured a motile cell state reflecting a malignant phenotype, as migration was as abundant as in MCF7 WT breast tumor cells.…”

“…Albeit RAC-1 is not a DNA-binding transcription factor, it has nuclear and cytoplasmic functions that regulate cellcycle progression (Olson et al, 1995), adhesion and migration (Ridley et al, 2003;Raftopoulou and Hall, 2004;Pankov et al, 2005). Thus, KPNA2 overexpression could be involved in malignant transformation, by RAC-1-binding or defining its nuclear concentration, which then aberrantly modulates relevant downstream effector cascades.…”

RhoA/ROCK-mediated switching between Cdc42- and Rac1-dependent protrusion in MTLn3 carcinoma cells

“…The loss of motility in C3T-or Y27632-treated MTLn3 cells could be in part due to excessive Rac activation, as expression of a constitutively active Rac mutant in MTLn3 (Table 2) and other cells lines [53] leads to a symmetrical, circumferential protrusion and decreased motility. The effects of Rho/ROCK inhibition on motility could also be due in part to changes in the regulation of adhesive structures, as maturation of focal adhesions is blocked by inhibition of ROCK, consistent with previous studies [13].…”

Control of gastrula cell motility by the Goosecoid/Mix.1/ Siamois network: Basic patterns and paradoxical effects

“…Interestingly, in primary fibroblasts and in macrophages, respectively, it is the modulation of Rac activity that switches similarly between polarization states (Pankov et al, 2005;Wheeler et al, 2006). It appears that not only gastrula cells, but also cells from various other origins, are bi-stable with respect to polarity, and poised to transit between states.…”

“…Within a single cell line, Rac activation can increase or decrease migration, depending on the substrate (Sander et al, 1998). Cell morphology is similarly affected: knockdown of Rac reduces lamellipodia number in fibroblasts (Pankov et al, 2005), but increases it in macrophages (Wheeler et al, 2006). Likewise, RhoA activation reduces lamellipodia number in stromal cells (Jaganathan et al, 2007) and leucocytes (Worthylake and Burridge, 2003), but increases it in epithelial cells (Danen et al, 2005).…”