A family affair: A Ral-exocyst-centered network links Ras, Rac, Rho signaling to control cell migration

Abstract

Cell migration is central to many developmental, physiologic and pathological processes, including cancer progression. The Ral GTPases (RalA and RalB) which act down-stream the Ras oncogenes, are key players in the coordination between membrane trafficking and actin polymerization. A major direct effector of Ral, the exocyst complex, works in polarized exocytosis and is at the center of multiple protein-protein interactions that support cell migration by promoting protrusion formation, front-rear polarization, and extra-cellular matrix degradation. In this review we describe the recent advancements in deciphering the molecular mechanisms underlying this role of Ral via exocyst on cell migration. Among others, we will discuss the recently identified cross-talk between Ral and Rac1 pathways: exocyst binds to a negative regulator (the RacGAP SH3BP1) and to the major effector (the Wave Regulatory Complex, WRC) of Rac1, the master regulator of protrusions. Next challenge will be to better characterize the dynamics in space and in time of these molecular interplays, to better understand the pleiotropic functions of Ral in both normal and cancer cells.

Keywords: Rac; Ral; Ras; Rho; Wave; exocyst; migration.

Figure 1.

The protein-protein interaction network of Ral-exocyst controlling migration and invasion. The exocyst, a major effector of Ral proteins, directly interact with several key regulators of protrusion formation (Wave Regulatory Complex, Arp2/3 complex, SH3BP1, paxillin), front-rear polarity (Par complex) and extra-cellular matrix degradation (WASH, IQGAP) or deformation (GEFH1), to drive cell migration and invasion.

Figure 2.

The cross-talk between RalB and Rac1 pathways during cell migration. While both RalA and RalB may participate to control cell migration, here we indicate RalB because its role is more robust and universal. RalB regulates assembly and localization of exocyst complex which in turn directly binds to a negative Rac1 regulator, the RacGAP SH3BP1, and to a major Rac1 effector, the Wave Regulatory Complex (WRC). RalB, exocyst, SH3BP1 and WRC, they all localize at the cell front in migrating cells even though the features and dynamics of their translocations appear different and need more investigation.

Figure 3.

Model for Wave Regulatory Complex (WRC) recruitment and activation. Via interaction with exocyst, WRC is recruited to the front plasma-membrane (1) where it is moderately activated by the existing Rac1-GTP and PIP3 molecules (2). Rac1-GTP retains WRC at the edge, exocyst dissociates from WRC and recycles in the cytosol (3). This initial WRC activation is sufficient to start protrusion (4). The positive feedback loop between actin filaments and Rac1^46,47 leads to sustained Rac1 activation and stronger WRC stimulation (5). During the protrusion progression, a fraction of the WRC complex is incorporated in the actin network to be recycled (6).