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  • Review Article
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Rap1 signalling: adhering to new models

Key Points

  • Rap1 is a close relative of the small GTPase Ras, and was identified in a screen for revertants of cells oncogenically transformed by mutant Ras.

  • Rap1 is activated — that is increased GTP-bound over GDP-bound — by a large variety of extracellular stimuli through several evolutionarily conserved guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs).

  • A striking GEF for Rap1 is Epac, a ubiquitously expressed GEF directly activated by cyclic AMP. Epac is therefore a novel cAMP target.

  • One of the reported functions of Rap1 is the binding to, and modulation of, the serine/threonine kinases Raf1 and B-raf, resulting in the modulation of extracellular signal-regulated kinase (ERK) and ERK-mediated transcriptional control, but conflicting results indicate that these interactions remain to be firmly established.

  • Genetic studies in lower eukaryotes, such as Drosophila melanogaster indicate that Rap1 might function in the regulation of cell migration and morphogenesis, but not in cell proliferation. In contrast to Ras, Rap1 seems not to function in the direct regulation of the single orthologue of Raf1/B-raf present.

  • Recent findings indicate that Rap1 is involved in the regulation of integrin-mediated cell adhesion. The mechanism of this regulation is still elusive.

  • The intracellular localization of Rap1 predominantly at the cytosolic site of intracellular membranes, like endosomes and secretory granules, might point to a role of Rap1 in the recruitment of components for vesicle formation and/or transport. This is also suggested by the function of the Rap1 orthologue in yeast, Bud1, in bud site selection.

Abstract

Ras-like GTPases are ubiquitously expressed, evolutionarily conserved molecular switches that couple extracellular signals to various cellular responses. Rap1, the closest relative of Ras, has attracted much attention because of the possibility that it regulates Ras-mediated signalling. Rap1 is activated by extracellular signals through several regulatory proteins, and it might function in diverse processes, ranging from modulation of growth and differentiation to secretion, integrin-mediated cell adhesion and morphogenesis.

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Figure 1: Ras-like small GTPases.
Figure 2: The Rap1 signalling network.
Figure 3: Regulatory proteins of Rap1.
Figure 4: Rap1 as a mediator of cyclic AMP signalling.
Figure 5: Role of Bud1 in bud site selection.

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Acknowledgements

We thank F. Wittinghofer, M. Peter, C. Buckley and M. Matsuda for many discussions and for sharing unpublished results, F. Zwartkruis en Boudewijn Burgering for discussions and critically reading the manuscript, and the other members of the lab for support. The work on Rap1 in our lab is supported by the Netherlands Organisation for Scientific Research (C.W. and A.L.W.), the Dutch Cancer Society, the Royal Academy of Sciences and the Netherlands Heart Foundation.

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Authors and Affiliations

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Related links

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DATABASE LINKS

Rap1

Krev-1

Raf

Rap1a

Rap1b

NGF

C3G

Crk

R-ras

Epac1

M-ras

CalDAG-GEF

Rap2

Nsp2

Ral

Tuberin

Rab5

GAPIP4BP

B-raf

RalGDS

EGF

interleukin-1

interleukin-2

phospholipase D

Rlf

Rgl

AF-6

zonula occludens 1

profilin

protein kinase B/Akt

CD31

H-ras

mitogen-activated protein kinase

phospholipase C

VLA5

Spa-1

HGF

SDF-1

LFA-1

Bud1

Cdc24

Cdc42

Bem1

Bud5

Bud2

FURTHER INFORMATION

Bos lab

SMART database

ENCYCLOPEDIA OF LIFE SCIENCES

G proteins

Glossary

DEP DOMAIN

(Dishevelled, Egl-10 and Pleckstrin). Domain of unknown function that is present in signalling proteins.

RBD

Ras association domain (RA) or Raf-like Ras-binding domain (RBD).

PDZ DOMAIN

(PSD-95, Dlg and ZO-1/2). Protein–protein interaction domain that binds particularly to carboxy-terminal polypeptides.

SH2 DOMAIN

(Src homology domain 2). Domain that interacts with phosphotyrosine-containing polypeptides.

ANERGIC T CELLS

T cells that are proliferatively unresponsive to antigenic restimulus.

FLUORESCENCE-RESONANCE ENERGY TRANSFER

Method to identify close neighbourhood of two proteins, each labelled with a different fluorescent group.

PAROTID GLAND

Salivary gland near the ear.

14-3-3 PROTEINS

Proteins that bind to two phosphoserine/threonine-containing polypeptides to form crosslinks.

ADHERENS JUNCTIONS

Cadherin-dependent cell–cell contacts.

GERM TUBE

Membrane extension used for mating.

MACROPINOCYTOSIS

Uptake of extracellular fluid by endocytosis.

αLβ2

Heterodimeric cell surface protein consisting of the integrin αL and β2 chains.

CD31 OR PLATELET-ENDOTHELIAL CELL ADHESION MOLECULE (PECAM)

Cell surface protein that can form homotypic interactions.

OPSONIZED PARTICLES

Particles covered with proteins that enhance uptake by phagocytosis.

NADH OXIDASE COMPLEX

Enzyme complex responsible for the respiratory burst to breakdown phagocytosed particles.

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Bos, J., de Rooij, J. & Reedquist, K. Rap1 signalling: adhering to new models. Nat Rev Mol Cell Biol 2, 369–377 (2001). https://doi.org/10.1038/35073073

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