From Ras to Rap and Back, a Journey of 35 Years

Abstract

Our laboratory has studied Ras and Ras-like proteins since the discovery of the Ras oncogene 35 years ago. In this review, I will give an account of what we have done in these 35 years and indicate the main papers that have guided our research. Our efforts started with the early analysis of mutant Ras in human tumors followed by deciphering of the role of Ras in signal transduction pathways. In an attempt to interfere in Ras signaling we turned to Rap proteins. These proteins are the closest relatives of Ras and were initially identified as Ras antagonists. However, our studies revealed that the Rap signaling network primarily is involved in spatiotemporal control of cell adhesion, in part through regulation of the actin cytoskeleton. More recently we returned to Ras, trying to interfere in Ras signaling by combinatorial drug testing using the organoid technology.

Figure 1.

Evolutionary timeline of the Ras family, Ras, Rap, and Ral proteins. The last eukaryotic common ancestor (LECA) likely contained already representatives of these proteins. Later duplications are responsible for the different members in mammalian cells. (From van Dam et al. 2011; adapted, with permission, from the authors.)

Figure 2.

Rap guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). Indicated are the domain structures of Rap-specific GEFs and GAPs. (From Bos et al. 2007; adapted, with permission, from the authors.)

Figure 3.

(A) Crystal structure of Epac 2 in the closed (left) and open (right) conformation. The gray area (right) represents the first cyclic adenosine monophosphate (cAMP) domain and Dishevelled, EGL-10, and pleckstrin (DEP) domain visualized by cryoelectron microscopy (Rehmann et al. 2006, 2008). (B) Structure of 8CPT-2′OMe-cAMP (007).

Figure 4.

Graphical summary of (A) Epac1-mediated regulation of radial stress fibers through the Radil-Rasip1-ArgGAP29 complex, and of (B) Rap2A-mediated intestinal brush borders formation (for explanation see text).