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doi: 10.1242/10.1242/jcs.00238

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Cellular functions of the Rap1 GTP-binding protein: a pattern emerges

Centre for Molecular Microbiology and Infection and Department of Biological Sciences, The Flowers Building, Room 2:41, Armstrong Road, Imperial College of Science, Technology and Medicine, London SW7 2AZ, UK

View larger version (83K): [in a new window]   Fig. 1. Amino-acid sequence of the human (Hs) Rap1a GTP-binding protein compared to the primary structures of its Drosophila melanogaster (Dm), Dictyostelium discoideum (Dd) and Saccharomyces cerevisiae (Sc/Bud1) homologs and three other human Ras subfamily members: Rap2a, R-Ras and H-Ras. Boxes define regions of identity between all sequences, whereas the overall homology is shown in blue. Notice the total identity between Rap1 homologs and Ras in the main effector-binding region, delineated by the red bar (amino acids 32-42). Also of note is the high degree of conservation in primary sequence amongst the 4 Rap1 homologs, with homology indicated in yellow. Significant homology is defined here as a score of over 85% in the Dayhoff PAM250 scale. For commodity, several stretches of sequence have been deleted from this alignment. These include the two N-terminal residues in Dd Rap1, the first 26 amino acids in R-Ras and two regions unique to Bud1. Arrowheads indicate the position of these latter two deletions, which correspond respectively to amino acids 171-226 (1) and amino acids 236-258 (2).

View larger version (26K): [in a new window]   Fig. 2. Many receptors and second messengers are coupled to the activation of Rap1 guanine nucleotide exchange factors (Rap1GEFs), and an increase in the cellular levels of active, GTP-bound Rap1. Abbreviations used in this figure: ADP, adenosine diphosphate; fMLP, formyl-methionine leucine phenylalanine; LPA, lysophosphatidic acid; DAG, diacyl glycerol; PDGF, platelet-derived growth factor; IFN-, alpha-interferon; TCR, T cell receptor; EphK, ephrin kinase; TNF, tumor necrosis factor alpha; IL-1, interleukin 1; LPS, lipopolysaccharide; NMDA, N-methyl-D-aspartate; GPCR, G-protein-coupled receptor; RTK, receptor tyrosine kinase (including kinase-associated receptors); DD-R, death-domain-associated receptor. The corresponding bibliographic references are given in the text body.

View larger version (24K): [in a new window]   Fig. 3. Rap1 downstream effectors and proposed roles in mammalian cells. Adhesion-dependent and -independent functions are separated for simplicity but could prove related, as discussed in the text. The Rap1 targets indicated in red have been ruled out from playing a role in Rap1-mediated integrin activation.

View larger version (17K): [in a new window]   Fig. 4. A speculative model for how Rap1 governs the functional activation of integrins. In resting blood cells, most integrins are kept inactive, possibly owing to conformational constraints in the cytoplasmic tails (bottom left). A small proportion of the integrin dimers display the thermodynamically unfavourable, active conformation and can bind their ligand (top left). However, if Rap1-GTP levels remain low, structural constraints (blue arrows) force the equilibrium towards the inactive form. Upon agonist stimulation, Rap1 is transiently converted to the active GTP-bound form (red arrows), exposing the effector-binding region(s), and one of its downstream targets (depicted in orange) directly or indirectly (through the yellow rod-shaped molecule) maintains the integrin in its active conformation. By contrast, Mn2+ treatment (grey arrow) does not activate Rap1, although endogenous levels of active Rap1 still control Mn2+-induced integrin activation. Rap1 activity is therefore required in all cases for ligand binding and outside-in signalling to take place, as suggested in this figure by the anchoring of the ligand-bound integrin to the actin cytoskeleton.