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Review
. 2018 Feb 1;8(2):a031468.
doi: 10.1101/cshperspect.a031468.

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

Johannes L Bos  1
Affiliations
Review

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

Johannes L Bos. Cold Spring Harb Perspect Med. .

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.

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Figures

Figure 1.
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.
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.
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.
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).
See this image and copyright information in PMC

References

    1. Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M. 1988. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 53: 549–554. - PubMed
    1. Altschuler DL, Peterson SN, Ostrowski MC, Lapetina EG. 1995. Cyclic AMP-dependent activation of Rap1b. J Biol Chem 270: 10373–10376. - PubMed
    1. Ando K, Fukuhara S, Moriya T, Obara Y, Nakahata N, Mochizuki N. 2013. Rap1 potentiates endothelial cell junctions by spatially controlling myosin II activity and actin organization. J Cell Biol 202: 901–916. - PMC - PubMed
    1. Asha H, de Ruiter ND, Wang MG, Hariharan IK. 1999. The Rap1 GTPase functions as a regulator of morphogenesis in vivo. EMBO J 18: 605–615. - PMC - PubMed
    1. Baas AF, Kuipers J, van der Wel NN, Batlle E, Koerten HK, Peters PJ, Clevers HC. 2004. Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD. Cell 116: 457–466. - PubMed

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