Cdc42 controls the polarity of the actin and microtubule cytoskeletons through two distinct signal transduction pathways

Abstract

Cdc42, a Rho family GTPase, is a key regulator of cell polarity. In Saccharomyces cerevisiae, it is required for polarized bud formation and pheromone gradient sensing, while in higher eukaryotes, it participates in asymmetric cell division, directional sensing during migration, and morphogenesis. Using a scratch-induced fibroblast migration assay, we previously showed that Cdc42 controls the polarization of both membrane protrusions and the Golgi/centrosome. We now find that Golgi/centrosome polarity is mediated through activation of the Par6/aPKC complex, as previously described in astrocytes. However, this complex is not involved in Cdc42-dependent polarization of protrusions, which instead is mediated by Pak acting through the Rac guanine nucleotide exchange factor, βPIX. Pak kinase activity is essential for spatially restricting Rac-dependent actin polymerization to the leading edge of the migrating cells, though it is not required for actin polymerization per se. We conclude that in migrating cells, Cdc42 co-ordinately regulates the polarity of the microtubule and actin cytoskeletons through two distinct pathways.

The tumour-suppressor Scribble dictates cell polarity during directed epithelial migration: regulation of Rho GTPase recruitment to the leading edge

“…In contrast, loss of Bazooka/Par3 in the context of activated Ras in the eye imaginal disc epithelium can give rise to invasive tumours in Drosophila (Pagliarini and Xu, 2003). In mammalian cells, the dissolution of cell-cell junctions following loss of Par3 (Chen and Macara, 2005) or Par6 (Ozdamar et al, 2005) has been proposed to promote migration and invasion of tumour cells, however, Par6/ aPKC complex function is required for migration of a number of cell types such as astrocytes and fibroblasts (Etienne-Manneville and Hall, 2001;Cau and Hall, 2005).…”

αPIX RhoGEF Supports Positive Selection by Restraining Migration and Promoting Arrest of Thymocytes

“…bPIX regulates formation of protrusions (14,(37)(38)(39), and overexpression of bPIX in fibroblasts and neurons alters the localization of bPIX itself, GIT1, Rac activity, and protrusions from a single leading edge to all around the cell periphery (37,39). Moreover, increased Rac activity in fibroblasts and epithelial cells correlates with multiple peripheral lamellae, or protrusions, and increased random motility (40).…”

Regulation of actin cytoskeleton dynamics by Arf-family GTPases

“…Early models suggested that PIX activated Rac and/or Cdc42, which then activated PAK [68]. Active PAK would then stimulate focal adhesion turnover and extension of lamellipodia, thereby promoting cell migration [67,69]. However, subsequent work determined that PAK can be activated directly by GIT in a GTPase-independent manner, calling into question whether Rac and Cdc42 activation is necessary [70].…”