Rap Signaling
The Rap proteins comprise a subfamily of the Ras-like small G-proteins, most closely related to Ras, which were originally found to antagonize Ras-induced cell transformation. Rap transduces extracellular stimuli to a variety of different processes, among
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Rap Signaling Willem-Jan Pannekoek and Johannes L. Bos
Abstract The Rap proteins comprise a subfamily of the Ras-like small G-proteins, most closely related to Ras, which were originally found to antagonize Ras-induced cell transformation. Rap transduces extracellular stimuli to a variety of different processes, amongst others cell–matrix adhesion, cell–cell adhesion, and actin dynamics. Here, we present an overview of the mechanisms that regulate activation, including guanine nucleotide exchange factors and GTPase activating proteins responsible for the regulation. We discuss the various biological functions that are controlled by Rap proteins and the molecular mechanism used by Rap1 to induce these responses. Keywords Rap1 • Rap2
11.1
Rap Proteins
Rap proteins were first identified by Pizon and coworkers in a search for Ras-related genes in a human cDNA library (Pizon et al. 1988). Five Rap isoforms exist in humans: Rap1A, 1B, 2A, 2B, and 2C, which share approximately 50 % sequence identity with Ras and as such are most closely related to the classical Ras proteins. The Rap1 isoforms are identical in “the business end” of the molecule (Fig. 11.1, termed “switch 1” and “switch 2”), i.e., the region that changes conformation upon binding to GDP or GTP and that interacts with guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and effectors (Bos et al. 2007). Within this region, one amino acid difference exists between the Rap2 isoforms. Six amino acids within this region are different between Rap1 and Rap2, an important one is W.-J. Pannekoek • J.L. Bos (*) Molecular Cancer Research and Cancer Genomics Netherlands, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands e-mail: [email protected] A. Wittinghofer (ed.), Ras Superfamily Small G Proteins: Biology and Mechanisms 1, DOI 10.1007/978-3-7091-1806-1_11, © Springer-Verlag Wien 2014
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on position 39 (S in Rap1, F in Rap2), as this residue allows specific GEFs and effectors to bind to Rap2 (Miertzschke et al. 2007; Nonaka et al. 2008; Yaman et al. 2009). Most differences between the Rap isoforms reside within the C-terminal hypervariable region (HVR). This region determines the subcellular localization of the protein in three ways (Prior and Hancock 2012): (1) the last four residues constitute the CAAX-motif (C ¼ cysteine, A ¼ aliphatic, X ¼ any amino acid). This CAAX-motif is recognized by either a farnesyltransferase or a geranylgeranyltransferase, which covalently attaches an isoprenoid (either farnesyl or geranylgeranyl) to the cysteine. These lipid modifications insert into lipid bilayers to target the protein to cell membranes. Rap1A, Rap1B, and Rap2B are geranylgeranylated, whereas Rap2A and Rap2C are farnesylated. (2) Rap1 proteins have a poly-basic region in the HVR that aid to membrane targeting. For instance, Rap1A contains two clusters of three lysine residues within the HVR, in which it differs subtly with Rap1
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