The small GTPase RhoB regulates endocytic trafficking of receptor tyrosine kinases

The small GTPase RhoB regulates endocytic trafficking of receptor tyrosine kinases (RTKs) and the non-receptor kinases Src and Akt. immune surveillance, atherosclerosis, arthritis and cancer progression [Raftopoulou and Hall, 2004; Ridley et al., 2003]. Crucial signaling events that promote cell migration are brought on by cell surface receptors producing in fine alterations in the business of the actin cytoskeleton. Among the many effector signaling molecules that alter actin business, the Rho GTPases play pivotal functions in regulating cell migration. This class of molecules, which includes Cdc42, Rac and Rho, function as binary changes that trigger formation of different cytoskeletal actin structures required for migratory behaviors. Specifically, Cdc42, Rac and Rho promote the formation of filopodia, lamellipodia and stress fibers, respectively, different structures required to drive cell movement [Hall, 1998; Heasman and Ridley, 2008]. Cdc42 and Rac are particularly important at the leading edge of the cell to regulate localized actin polymerization and membrane protrusions. Actin remodeling at sites on the leading edge is usually thought to occur as a result of a redistribution of signaling molecules to spatially restricted areas in response to extracellular cues. How this redistribution occurs Telaprevir is usually incompletely comprehended, but receptor-mediated endosome formation and trafficking have been implicated in the process [Maxfield and McGraw, 2004; Polo and Di Fiore, 2006]. Endocytosis of receptor tyrosine kinases (RTKs) such as the PDGFR not only promotes cell proliferation but also actin remodeling and cell migration. PDGFR promotes formation of migratory cellular protrusions, such as peripheral ruffles and circular dorsal ruffles by stimulating rearrangement of actin filaments [Andrae et al., 2008; Buccione et al., 2004]. As the major driving pressure in migration, the extension of leading edge lamellipodia formed by Rac activation serve as pliable and dynamic structures. As another necessary part of the actin dynamic at the leading edge, dorsal circular ruffles function as important sites in directing spatially restricted actin remodeling adjacent to lamellipodia extension [Buccione et al., 2004]. How receptor-mediated endocytosis regulates these processes remains evasive. It has been shown that the regulators of endocytosis, such as dynamin and Rab5, are required for actin mechanics leading to the formation of circular ruffles in response to RTK activation [Lanzetti et al., 2004; Orth and McNiven, 2003]. One recent study has suggested that after activation, Rab5-mediated endocytic trafficking of Rac is usually important for the Rabbit polyclonal to PPP1R10 spatial restriction of signaling in cell migration [Palamidessi et al., 2008]. These studies support the concept that during receptor-mediated endocytosis the endosomal system serves as an important assembly site for the formation of signaling complexes that direct migration. RhoB, a member of the Rho small GTPase family, has selective functions in endosomal trafficking. RhoB localizes to both the plasma membrane and the membrane of early and late endosomes [Adamson et al., 1992; Fernandez-Borja et al., 2005; Mellor et al., 1998; Rondanino et al., 2007]. Studies demonstrating the role of RhoB in the endocytic pathway show that, in different settings, RhoB facilitates the trafficking of signaling molecules including RTKs, Telaprevir Akt and Src to the cell surface, the nucleus, or the lysosome [Adini et al., 2003; Gampel et al., 1999; Neel Telaprevir et al., 2007; Sandilands et al., 2004; Wherlock et al., 2004]. In recent work, we reported that RhoB is usually required for PDGF-stimulated proliferation of primary vascular easy muscle cells (VSMCs) by promoting the endosomal trafficking of active Telaprevir Akt, ERK and Src into the nucleus [Huang et al., 2007]. RhoB loss did not alter PDGFR protein levels, but did affect the phosphorylation and trafficking of this receptor..