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
(e-mail: e.caron{at}ic.ac.uk)
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Summary |
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Key words: Rap1, Adhesion, Integrin, Small GTP-binding proteins
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Introduction |
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Rap1 belongs to the Ras subfamily of small GTP-binding proteins, which is
considered to control cell growth, differentiation and survival. The Ras
subfamily consists of 19 members, the best characterized of which are further
divided into the classic Ras (H-Ras, K-Ras, N-Ras), R-Ras, Ral and Rap groups.
The Rap subgroup contains two pairs of quasi-identical GTP-binding proteins
(Rap1A and Rap1B; and Rap2A and Rap2B), which differ by only a few residues
(95% and 90% identical at the amino acid level, respectively). By contrast,
Rap1 and Rap2 proteins are only 60% identical to each other, showing
noticeable variations at their C-terminus
(Reuther and Der, 2000;
Takai et al., 2001
). This
could impact on their subcellular localization and also explain their
different sensitivities to RapGEFs (Rap
guanine-nucleotide-exchange factors) or their
distinct profiles of downstream targets (e.g. Van der Berghe et al., 1997;
Janoueix-Lerosey et al.,
1998
).
Historically, our understanding of the cellular function of individual Ras
subfamily members has been shaped mainly by comparisons with H-Ras or K-Ras.
Rap1 is no exception, and it took about 15 years to dissociate the cellular
functions of Rap1 and Ras. Three or four major findings have led to our
current incomplete understanding of Rap1 function. Human
RAP1 was originally cloned by virtue of its homology with the
Drosophila RAS3 allele (Pizon et
al., 1988), later renamed Drosophila RAP1. The following
year, Rap1 was found to be identical to Krev-1, a cDNA able
to revert the phenotype of K-Ras-transformed cells
(Kitayama et al., 1989
). One
hypothesis advanced at the time to explain this major finding was that the
sequence-related, 53% identical, Rap1 and Ras compete for downstream targets.
Overexpressed Rap1 was soon found to be unable to activate Raf-1, contrarily
to Ras (Cook et al., 1993
).
Seemingly confirming the original postulate, this result quickly led to the
persistent view that Rap1 is merely a Ras antagonist that forms non-productive
complexes with Ras effectors. Nevertheless, recent biochemical, cellular and
developmental evidence unambiguously reveals that Rap1 has at least one
Ras-independent function in a variety of cellular systems: the control of
adhesion-related events.
Rap1 biochemistry, as well as the trail of discoveries leading to the
recognition of a positive, Ras-independent role for Rap1 and some of the
persisting ambiguities in the field have been well analyzed recently
(Bos et al., 2001). Here, I
only briefly summarize the essential biochemical features of Rap1, focusing
instead on its specific cellular functions. A variety of key findings obtained
in the past three years suggests a conserved role for Rap1 in integrating
extracellular signals to allow the organization of cell architecture.
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Rap1: a close relative of Ras, but with a distinctive character |
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The number of reports on Rap1 has increased exponentially in recent years,
leading to the realisation that a considerable variety of stimuli acting
through the whole spectrum of signalling pathways activate Rap1
(Fig. 2). The latest additions
to this list include adhesive surfaces
(Ohba et al., 2001), ephrin
and ephrin kinases (Prevost et al.,
2002
), adenosine diphosphate
(Woulfe et al., 2002
;
Lova et al., 2002
), the NMDA
neurotransmitter (Zhu et al.,
2002
), hyperosmotic and cold stresses
(Kang et al., 2002
),
interleukin-1 (Palsson et al.,
2000
), stromal cell-derived factor-1 [SDF-1
(McLeod et al., 2002
)], CD98
crosslinking (Suga et al.,
2001
), CD31 crosslinking
(Reedquist et al., 2000
),
lipopolysaccharide (Caron et al.,
2000
; Schmidt et al.,
2001
) and antigen-loaded antigen-presenting cells [APCs
(Katagiri et al., 2002
)].
R-Ras, another member of the Ras subfamily of small GTP-binding proteins that
has been implicated in the control of integrin-mediated adhesion
(Zhang et al., 1996
), was
recently linked to Rap1. Although it remains to be established whether active
R-Ras (or an elusive R-Ras activator) is able to activate Rap1 in cells,
RapGAP expression blocks R-Ras-induced effects in several cell types, which
suggests that Rap1 acts downstream of R-Ras
(Self et al., 2001
). The
parallel discovery of numerous, evolutionarily conserved RapGEFs able to relay
signals from extracellular stimuli and second messengers to Rap1 (reviewed in
Bos et al., 2001
;
Gao et al., 2001
), as well as
specific RapGAPs (Polakis et al.,
1991
; Kurachi et al.,
1997
; Chen et al.,
1997
; Pak et al.,
2001
), reinforced the possibility that Rap1 has a central function
in signal transduction processes.
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Rap1 has multiple cellular roles, most of which are adhesion related |
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Adhesion-independent functions
Rap1 signalling has contrasting effects on cell growth and proliferation
and activation of the ERK
(extracellular-signal-regulated kinase) MAP
kinase pathway. Rap1 activation potentiates the response to mitogenic stimuli
in thyroid follicular cells and antigen-challenged thymocytes
(Ribeiro-Neto et al., 2002;
Sebzda et al., 2002
), and
links cyclic AMP signalling to the regulation of ERK activity and cell
proliferation (Schmitt and Stork,
2001
; Ribeiro-Neto et al.,
2002
; Lou et al.,
2002
; Laroche-Joubert et al.,
2002
). Whether Rap1 activates (e.g. in neuronal and neuroendocrine
cells), inhibits or has no effect on Erk activation, however, seems to depend
on the cell type and the experimental conditions used
(Bos et al., 2001
;
Schmitt and Stork, 2001
;
Sebzda et al., 2002
;
Klinger et al., 2002
;
Laroche-Joubert et al.,
2002
).
Another seemingly adhesion-independent function of Rap1 is exemplified by
yeast cells, where the Rap1 homolog Bud1p/Rsr1p controls bud-site selection
and interacts with upstream regulators of the actin cytoskeleton
(Gulli and Peter, 2001). Bud1p
is localised on internal membranes and at the plasma membrane, where it is
enriched at sites of polarized growth and budding
(Park et al., 2002
). Local
enrichment at the plasma membrane could be specified by Bud5p, the yeast
RapGEF, which is recruited to the bud site in a cell-cycle-dependent way.
Bud5p recruitment itself is driven by other proteins, noticeably by
Ax12p/Bud10p, a transmembrane protein and Bud5p-binding partner thought to act
as an internal spatial landmark (Kang et
al., 2001
).
Adhesion-related functions
The evidence implicating Rap1 in the control of cell adhesion is compelling
and extends from Dictyostelium to mammalian cells. Krev-1 was first
characterized as a cDNA inducing `flat', that is, morphologically
non-transformed, strongly adherent revertants in K-Ras-transformed cells
(Kitayama et al., 1989), and
it is now well established that interfering with Rap1 GTP cycle has profound
effects on a wide range of adhesive processes: morphogenesis, phagocytosis,
cell-cell adhesion, cell migration and spreading.
Overexpression of membrane-targeted RapGEFs or active forms of Rap1 induces
cell spreading in 293T cells, whereas low levels of active Rap1, achieved
through overexpression of either RapGAP or the dominant-negative mutant
N17Rap1 cause cell rounding (Tsukamoto et
al., 1999). Similarly, the activated V12Rap1 mutant induces
spreading of Dictyostelium cells
(Rebstein et al., 1997
) and
the integrin-dependent spreading of a variety of haematopoietic cells (see
below). As expected, Rap1 has opposite effects on spreading and cell motility,
and mouse embryo fibroblasts derived from C3G-knockout animals show delayed
cell spreading and increased motility, both of which are suppressed by
overexpressed active Rap1 (Ohba et al.,
2001
).
The profound influence of Rap1 signalling on cell morphology is also
evident in vivo: Rap1 mutations disrupt normal cell shape and morphogenesis in
the eye, ovary and wing of Drosophila embryos
(Hariharan et al., 1991;
Asha et al., 1999
;
Knox and Brown, 2002
). The
most recent data suggest that Rap1 regulates the position of adherens junction
markers (DE-cadherin, ZO-1 and canoe/AF-6, a downstream target of Rap1) at the
apical face of the epithelium lining the wing. Remarkably, in Rap1-mutant
cells, the cell junction proteins concentrate on one side of the cell, whereas
Rap1-GFP is enriched at the apical junctions in wild-type cells.
Interestingly, Rap1GFP is also preferentially recruited to the boundary
between the two daughter cells after cytokinesis; this is reminiscent of the
S. cerevisiae situation, where the Rap1 exchange factor Bud5p is
enriched at the cell division site (Kang
et al., 2001
). Finally, Rap1 controls several specialized types of
cell-cell adhesion in immune cells, such as the immunological synapses that
form at the interface between T cells and APCs
(Katagiri et al., 2002
) and
integrin-dependent macrophage phagocytosis
(Caron et al., 2000
). Two
additional facts regarding Rap1 and phagocytosis are worth noting: first, Rap1
also regulates phagocytosis of bacteria and latex beads in
Dictyostelium (Seastone et al.,
1999
); second, in mammalian cells, Rap1 is found associated with
maturing phagosomes (Pizon et al.,
1994
; Garin et al.,
2001
).
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Rap1 controls inside-out signalling to integrins |
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Rap1 regulates functional activation of several integrin heterodimers:
4ß1 (VLA-4),
5ß1 (VLA-5),
Lß2 (LFA-1,
CD11a/CD18),
Mß2 (CR3, CD11b/CD18) and
IIbß3
(Reedquist et al., 2000
;
Caron et al., 2000
;
Katagiri et al., 2000
;
Arai et al., 2001
;
Sebzda et al., 2002
;
Bertoni et al., 2002
). Active
Rap1A is sufficient to induce integrin function in T-cell- and macrophage-like
cell lines (Reedquist et al.,
2000
; Caron et al.,
2000
; Katagiri et al.,
2000
; Schmidt et al.,
2001
), as well as in primary T-cells and megakaryocytes
(Sebzda et al., 2002
;
Bertoni et al., 2002
), even in
the absence of extracellular agonists. Conversely, expression of Rap1GAP or
Rap1(N17) abolishes the ability of integrins to bind to their ligands, even in
agonist-stimulated cells. In the various models, all the agonists that elicit
inside-out signalling increase the levels of endogenous GTP-bound Rap1 in the
absence of integrin ligand. None of the Rap1 effects are attributable to
measurable changes in integrin expression. Finally, most studies used
read-outs that exclude an impact of Rap1 signalling downstream of ligand-bound
integrins. The studies mentioned above used the binding of a soluble ligand
(Katagiri et al., 2000
;
Bertoni et al., 2002
;
Sebzda et al., 2002
), a small
phagocytic target (Caron et al.,
2000
) or a conformation-specific antibody
(Reedquist et al., 2000
;
Katagiri et al., 2000
;
Bertoni et al., 2002
), rather
than mere adhesion to a substratum, which potentially results from both
inside-out and outside-in signalling. Altogether, these data establish a
general role for Rap1 in the control of inside-out signalling to
integrins.
The molecular mechanism underlying this spectacular effect of Rap1 remains
unknown. First, the exact meaning of functional activation, that is, whether
inside-out signalling induces changes in integrin affinity, avidity or both,
is controversial (Hughes and Pfaff,
1998; van Kooyk and Figdor,
2000
). The studies on Rap1 and integrin activation have failed to
answer this question, because changes in integrin affinity
(Katagiri et al., 2000
;
Reedquist et al., 2000
) and
avidity (Sebzda et al., 2002
)
were observed in the case of the LFA-1 integrin. Second, the downstream target
mediating the effect of Rap1 on inside-out signalling remains unknown. Several
candidates (shown in red on Fig.
3) have been ruled out, on the basis of either the inability of
specific inhibitors of the ERK MAP kinase, PI3K and PLC signalling pathways to
inhibit or the ability of active RalGEF to mimic Rap1-induced effects
(Self et al., 2001
;
de Bruyn et al., 2002
). An
exciting new finding, however, is that activation of integrins in Jurkat T
cells by Mn2+ or activatory anti-LFA-1 or anti-VLA-4 antibodies is
still Rap1-sensitive despite being unable to elevate Rap1 GTP levels
(de Bruyn et al., 2002
). These
results led the authors to suggest that Rap1 controls the availability of
active integrins for productive binding. One possible model for how Rap1
governs both the activation and functional availability of integrins is
depicted in Fig. 4. In resting
blood cells, most surface-expressed integrins are inactive, therefore unable
to bind their ligands. Functional activation converts the inactive integrin
into a ligand-binding heterodimer, a spontaneously unfavourable process that
involves major conformational changes in the extracellular domains of both
and ß chains (Xiong et al.,
2001
; Beglova et al.,
2002
) and probably also in their cytoplasmic domains
(Haas and Plow, 1997
;
Vinogradova et al., 2002
).
Accordingly, the three-dimensional conversion of the extracellular domains
into a ligand-binding unit is elicited either directly by Mn2+,
that is, from the outside the cell, or after agonist stimulation, by the
combination of inside-out signalling, structural changes to the integrin
cytoplasmic domains and propagation of these changes to the extracellular
domains. Remarkably, the presence of active, GTP-bound Rap1 is required in the
two activation scenarios, which suggests that Rap1 activity is necessary to
stabilize the integrin in an `active' conformation. Rap1 could promote the
interaction of the integrin cytoplasmic domains with an undefined binding
partner. Whether the postulated integrin-binding partner is a direct Rap1
effector remains to be clarified.
|
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Concluding remarks |
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Two immediate challenges in Drosophila and in mammals are to
identify the effector mechanisms mediating the various Rap1 functions and to
understand how Rap1, which is activated in the perinuclear region, exerts most
of its effects at the cell surface. A striking common feature of the various
Rap1 functions described here is their presence upstream of a Rho GTPase
signalling pathway. This is certainly true for bud selection in yeast
(Gulli and Peter, 2001), for
ß2-dependent phagocytosis
(Caron and Hall, 1998
;
Caron et al., 2000
), for
integrin signalling (Schoenwaelder and
Burridge, 1999
) and probably also for cadherin-based adhesion
(Braga, 2000
;
Knox and Brown, 2002
;
Magie et al., 2002
). By
analogy with the situation in yeast, one might speculate that Rap1 is needed
to recruit a GEF for a Rho GTPase at sites of cell-cell or cell-matrix
contacts and thus enables the stabilisation of adhesive structures.
Understanding just how far these similarities extend will be a major task for
the coming years.
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Acknowledgments |
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