Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Rd, La Jolla, CA, 92037, USA
* Author for correspondence (e-mail: stupack{at}scripps.edu)
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Summary |
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Key words: Cell adhesion, Integrin, Apoptosis, Survival, Caspase
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Introduction |
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The life and death decision at the cellular level is controlled by
environmental cues, including death-receptor (DR) ligands
(Ashkenazi and Dixit, 1999) and
growth factors (Dvorak et al.,
1995
; Eliceiri,
2001
), as well as physical stimuli such as mechanical stress
(Ingber, 1992
) or radiation
(Wahl and Carr, 2001
). This
decision is profoundly influenced by the components of the extracellular
matrix (ECM), which can change dynamically during differentiation, development
and other tissue-remodeling events. Cell adhesion receptors and new ECM
proteins, deposited from intracellular stores or synthesized de novo
(Brown et al., 1993
;
Petersen et al., 1998
)
interact with both pre-existing and proteolytically exposed sites in the
assembled ECM (Davis, 1992
;
Xu et al., 2001
). The ongoing
remodeling presents a constantly changing environment, contrasting with the
static ECM in `resting' tissues and presents new information to cells that
governs their behavior. The principal adhesion receptors that convey this
information are the integrins.
Integrins are heterodimeric receptors for cell-surface adhesion molecules
and ECM proteins. Different and ß subunits are expressed in
limited combinations (Rupp and Little,
2001
) and exhibit different ligand specificities
(Table 1). The integrins that a
given cell expresses therefore control the repertoire of ECM components with
which the cell can interact. Integrins bind to ligands in a manner that is
dependent upon both affinity and avidity and is influenced by ligand
conformation and the capacity to anchor and array (multimerize) within the
pre-existing ECM. Thus, different ligands, or different forms of a particular
ligand, can transmit distinct signals to a cell through the same integrin
(Geiger et al., 2001
;
Koo et al., 2002
;
Stupack et al., 1999
).
Because ECM components may be recognized by more than one integrin,
competitive or cooperative binding among different integrin heterodimers adds
an additional layer of complexity to cellular responses to the ECM.
|
Anchorage dependence has long been recognized as a requirement for cell
viability (reviewed by Frisch and
Ruoslahti, 1997). Integrins govern cellular adhesion and shape,
which are critical factors in the cellular response to survival factors
(Ingber, 1992
;
Meredith et al., 1993
). The
integrin requirement for growth factor signaling is partly explained by the
physical association of several growth factor receptors with integrins
(Borges et al., 2000
;
Falcioni et al., 1997
;
Lee and Juliano, 2000
;
Miyamoto et al., 1996
;
Eliceiri, 2001
). However,
integrins also transmit signals directly through ligation-dependent
recruitment of non-receptor tyrosine kinases from the focal adhesion kinase
(FAK) and Src families, leading to the activation of several major cell
signaling pathways (Fig. 1).
The consequent downstream signals, especially via the mitogen-activated
protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways, are
critical for regulation of the cyclin-dependent kinases (CDKs) and cell cycle
progression (reviewed in Schwartz and
Assoian, 2001
). Since disruption of CDK signaling can result in
cell cycle arrest, leading to apoptosis, integrin-sustained cell cycle
signaling presents a basic mechanism by which integrins promote cell
survival.
|
Cells denied adhesion undergo apoptosis far more rapidly than cells denied
growth factors. This type of apoptosis (anoikis) results from a variety of
events (Frisch and Francis,
1994). Cells in suspension reorganize cytoskeletal architecture
(Boudreau and Jones, 1999
;
Flusberg et al., 2001
), alter
growth factor receptor and death receptor distribution and activity
(Aoudjit and Vuori, 2001
;
Arora et al., 1995
;
Finbloom and Wahl, 1989
;
Schleiffenbaum and Fehr,
1990
) and membrane lipid composition
(Schulze et al., 2001
),
elevate cyclic AMP levels, uncouple GTPase signaling
(Howe and Juliano, 2000
;
Lin et al., 1997
;
Schwartz and Shattil, 2000
)
and alter nuclear transcription (Sadek
and Allen-Hoffmann, 1994
;
Segaert et al., 1998
;
Vitale et al., 1999
). These
distinct events provide a formidable array of apoptotic triggers that insure
that unanchored cells remain non-viable. One reasonable explanation for the
wide variety of conflicting anoikis data
(Frisch and Ruoslahti, 1997
;
Frisch and Screaton, 2001
) is
that the `specific' apoptotic pathway triggered in a given cell type reflects
the dominant apoptosis pathway in the cell studied. A precise mechanistic role
for integrins in anoikis is therefore elusive, although, clearly,
integrin-mediated adhesion prevents these forms of death.
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Integrin-mediated `stress relief' |
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Integrins preserve cell viability in response to stress at several levels.
Signaling by integrins regulates both the expression and activity of several
members of the Bcl-2 protein family, affecting the abundance, function and
localization of these proteins. The ligation of integrins 5ß1 or
vß3, but not
vß1, leads to increased expression of
Bcl-2 (Matter and Ruoslahti,
2001
) and increased resistance to serum withdrawal.
Integrin-mediated survival is disrupted by dominant interfering Shc, PI
3-kinase or protein kinase B/Akt constructs
(Fig. 2), which suggests a
critical role for the PI 3-kinase/Akt pathway. Akt activation induces
transcription of the Bcl-2 homolog Bclxl
(Gauthier et al., 2001
;
Leverrier et al., 1999
). This
probably occurs because of signaling via the NF
B pathway, since several
prosurvival Bcl-2 proteins are regulated by this nuclear transcription factor
(Duriez et al., 2000
;
Grad et al., 2000
). NF
B
translocation to the nucleus is driven by integrin ligation, although the
particular integrin heterodimer that activates NF
B activation appears
to be cell type specific (Bearz et al.,
1998
; de Fougerolles et al.,
2000
; Lin et al.,
1995
; Ramarli et al.,
1998
; Scatena et al.,
1998
).
|
At the same time as inducing anti-apoptotic proteins, integrin-mediated
signals block the induction of death by proapoptotic Bcl-2 proteins. In
addition to triggering the PI 3-kinase/Akt pathway, integrin-mediated Ras
activation also results in the activation of the Raf/Mek/ERK pathway
(Fig. 3)
(Giancotti and Ruoslahti,
1999; Schlaepfer et al.,
1999
). Both Akt and Raf phosphorylate Bad (at Ser 112 and Ser 136,
respectively) (Fang et al.,
1999
; Hayakawa et al.,
2000
), promoting its binding and sequestration by members of the
14-3-3 protein family (Petosa et al.,
1998
). Mechanistically, phosphorylation-based translocation events
may be a common means of regulating proapototic Bcl-2 protein function, since
Bax also redistributes from the mitochondrial compartment to the cytoplasm as
a consequence of integrin-mediated substrate attachment
(Gilmore et al., 2000
).
|
Phosphorylation of Bcl-2 by MAP kinases, such as ERK1/2 and JNK, appears to
be more complicated. Phosphorylation of Bcl-2 at Thr 56, Thr 74 or Ser 84
(ERK1/2 sites) protects Bcl-2 from ubiquitin-targeted proteolysis, thus
effecting increased Bcl-2 accumulation and promoting cell survival
(Breitschopf et al., 2000).
Bcl-2 phosphorylation by ERK1/2 or JNK at Ser 70 enhances Bcl-2 anti-apoptotic
function after growth factor withdrawal
(Deng et al., 2001
) yet
compromises survival in response to the paclitaxel
(Srivastava et al., 1999
).
This conflict in results in mirrored in JNK activation studies, since JNK
activation in response to loss of adhesion
(Frisch et al., 1996
) or
chemotherapeutic agents (Avdi et al.,
2001
; Mandlekar et al.,
2000
) is proapoptotic but JNK activation downstream of
fibronectin-binding integrins suppresses apoptosis after serum withdrawal
(Almeida et al., 2000
).
Ligation of integrin vß3 may also suppress the expression of
the proapoptotic protein Bax, possibly via downregulation of the
transcriptional activity of p53
(Stromblad et al., 1996
).
Accordingly, glioma, melanoma and endothelial cells that express
vß3 integrins (in the context of an appropriate ECM), have
elevated Bcl-2 to Bax ratios and display increased survival in response to
stress both in vivo and in vitro
(Petitclerc et al., 1999
;
Uhm et al., 1999
).
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Integrin signaling is coordinated with other cellular responses to stress |
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There are now several examples of integrin signaling interacting with
chaperone functions in the cell. Integrinmediated actin remodeling promotes
phosphorylation and dephosphorylation of the heat shock protein Hsp27
(Polanowska-Grabowska and Gear,
2000), an anti-apoptotic chaperone that stabilizes actin dynamics
but also prevents mitochondrial release of cytochrome C and binds and
inactivates caspase 3 (Paul et al.,
2002
). Integrin ligation also influences binding of Hsp90
(Gear et al., 1997
), an
important cofactor for activity of the serine/threonine kinases Raf-1 and Akt,
to its targets (Hostein et al.,
2001
). The precise roles of other heat shock proteins, such as
hsp60, which appears to activate integrin
3ß1
(Barazi et al., 2002
) and
Hsp70, which binds Hsp90, caspase 3 and BAG (Bcl-2 athanogene) proteins, are
less well characterized.
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Life after cytochrome C release |
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Activated Akt directly phosphorylates and inactivates human caspase 9 at
S196; however, this site is not conserved in other species and it does not
appear that this is a general mechanism by which Akt promotes survival
(Fujita et al., 1999). Akt
also phosphorylates both nuclear factors (including FKHRL)
(Brunet et al., 1999
) and the
apoptosome scaffold protein Apaf-1 (Zhou
et al., 2000
), which may influence proapoptotic factor expression
and/or apoptosome formation. Integrin-mediated activation of Akt proceeds via
several mechanisms downstream of PI 3-kinase, including via integrin-linked
kinase (ILK) (Persad et al.,
2001
) and the phosphoinositide-dependent kinases (PDKs)
(Parise et al., 2000
). Akt is
negatively regulated by the action of the phosphatase PTEN on itself as well
as ILK, PtdIns(1,4,5)P3, FAK and Shc
(Yamada and Araki, 2001
).
Notably, lack of PTEN activity leads to increased cellular resistance to
apoptosis and a decreased requirement for integrin-mediated adhesion to
maintain cell viability, whereas, conversely, overexpression of PTEN
sensitizes cells to apoptosis and increases the integrin-adhesion requirement
(Lu et al., 1999
;
Tamura et al., 1999
).
Akt also phosphorylates and activates mTOR and its target p70S6 kinase,
critical regulators of CAP-dependent translation in the cell
(Scott et al., 1998).
Activated mTOR phosphorylates 4E-BPI
(Gingras et al., 1998
) in
cooperation with MEK (Herbert et al.,
2002
), preventing it from sequestering the CAP-dependent
translational initiator eIF4E.
Blockage of CAP-dependent translation by inhibition of Akt or mTOR mimics
growth factor deprivation and presents a mechanism by which cells sense this
stress. Conversely, overexpression of eIF4E prevents apoptosis and allows
growth-factor-independent cell growth
(Polunovsky et al., 1996).
Importantly, antagonism of integrin
vß3 (and possibly other
integrins) results in inhibition of both MEK activity in vivo
(Eliceiri et al., 1998
) and
mTOR activity and CAP-dependent translation in vitro
(Maeshima et al., 2002
).
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Integrins and the extrinsic death pathway |
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Integrin-mediated remodeling of the actin cytoskeleton is also likely to
play a major role in regulating the extrinsic apoptosis pathway. The type I
extrinsic pathway is modulated by the actin cytoskeleton
(Algeciras-Schimnich et al.,
2002). Dysregulation of actin with cytochalasin B results in
lateral clustering of DR1 (Fas) and its association with disrupted actin
filaments (Kulms et al.,
2002
). Similarly, simultaneous ligation of DRs and integrins
potentiates apoptosis, possibly because the coordinated actin remodeling
facilitates DISC formation (Aoki et al.,
2001
; Krzyzowska et al.,
2001
; Moreno-Manzano et al.,
2000
). This result may provide a context for the observation that
the DR ligands TNF
and FAS physically associate with ECM proteins such
as fibronectin. Disruption of integrin adhesion, which results in actin
remodeling, may similarly contribute to the FADD-dependent caspase 8
activation observed during anoikis
(Frisch, 1999
).
By contrast, stable integrin adhesion that sustains cytoskeletal integrity
appears to block the extrinsic apoptosis pathway. In this case, integrin
signaling, probably via ERK1/2, upregulates the caspase 8 inhibitor c-FLIP and
decreases the expression and activity of both Fas and Fas ligand on
endothelial cells (Aoudjit and Vuori,
2000). Thus, integrins may either promote or block apoptosis
triggered by the extrinsic pathway in a manner that is almost certainly
dependent upon the cells' current cytoskeletal status.
In addition to influencing susceptibility to DR-mediated apoptosis,
integrins may also promote a form of cell death similar to the type I
extrinsic pathway. Non-ligation or antagonism of vß3 or ß1
integrins can lead to caspase-8-dependent apoptosis among attached cells in
vivo (Brooks et al., 1994
;
Storgard et al., 1999
) and in
vitro (Kozlova et al., 2001
;
Stupack et al., 2001
;
Bonfoco et al., 2000
;
Brassard et al., 1999
;
Kuzuya et al., 1999
). This
form of apoptosis, called integrin-mediated death (IMD), appears to result
from the clustering of the integrins themselves rather than DRs. Although
actin, integrin and caspase 8 colocalize in complexes on dying cells, DRs and
the adaptor FADD are not observed
(Stupack et al., 2001
)
(D.G.S. and D.A.C., unpublished). Moreover, dominant interfering forms of
DD/DED adaptors, such as FADD, catalytically inactive caspase 8 and PEA-15, do
not block IMD as they do other forms of the extrinsic apoptosis pathway.
However, in common with DRs, integrins can cluster in a cytoskeleton-regulated
manner, independently of ligation or focal adhesion formation and are
available to bind to ligands or antagonists
(Byzova et al., 2000
;
Grabovsky et al., 2000
;
van Kooyk and Figdor,
2000
).
Whether an integrin-bound protein acts as a ligand or an antagonist is
dependent upon the context of the binding event. The transmission of
integrin-mediated signals is strongly dependent upon a mechanical element or
physical resistance factor (Schwartz,
2001; Vogel et al.,
2001
). Soluble ligands, in general, provide little mechanical
resistance and can be endocytosed through integrin-applied forces
(Nemerow and Cheresh, 2002
).
With few exceptions, these signals are incomplete, failing to recruit the full
complement of signaling proteins found in substrate-immobilized integrin
contacts (Miyamoto et al.,
1996
). Although sufficient to mediate internalization of
integrin-binding viruses (Li et al.,
2000
), the abortive nature of signaling by soluble
ligands/antagonists ultimately conveys `negative' or unproductive signals to
the cell regarding its environment
(Fenczik et al., 1997
;
Klinowska et al., 1999
). This
may be one reason that plasma-borne ECM proteins (including fibronectin,
fibrinogen and vitronectin) do not serve as integrin ligands in their native
soluble state but rather require conformational changes associated with
deposition or denaturation to reveal integrin-binding sites
(Narasimhan and Lai, 1989
;
Tomasini and Mosher, 1988
;
Zamarron et al., 1990
).
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Do integrins communicate with the DED? |
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A second link between integrin-mediated signaling pathways and DR-mediated
signaling pathways may be the DED-containing protein PEA-15. Identified in
astrocytes as a PKC substrate (Araujo et
al., 1993), PEA-15 acts both as a modulator of apoptosis
(downstream of PKC and/or calcium/calmodulin-dependent kinase II)
(Condorelli et al., 1998
) and
as a regulator of integrin function
(Ramos et al., 1998
).
Overexpression of active Raf-1 or H-Ras suppresses the integrin conformational
change necessary for efficient ligand binding
(Ramos et al., 1998
).
However, overexpression of PEA-15 relieves the H-Ras/Raf-1-induced blockage
but activates and sequesters ERK1/2 in the cytosol
(Formstecher et al., 2001
).
Different domains of PEA-15 appear to be involved in integrin regulation and
apoptosis the DED is sufficient to inhibit the extrinsic apoptosis
pathway but is insufficient to restore integrin function. However, PEA-15
expression also increases PKC activity
(Condorelli et al., 2001
),
which could affect caspase 8 activation and integrin signaling
(Keely et al., 1999
)
independently.
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Conclusions |
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Why should integrins preserve cell viability under conditions that might otherwise kill the cells? Strong integrin interactions between the local ECM and the cell might indicate to the cell that it is well suited to its immediate environment, regardless of the presence of proapoptotic insults. Thus, if local adverse conditions should be overcome, the exogenous stress is relieved, or is transient in nature, the cells present in the stressed tissue can be rescued rather than lost and/or replaced. Conversely, cells lacking the expression of integrins appropriate to the local ECM are more susceptible to stress and succumb more rapidly to apoptosis. Excessive trauma to the tissue, resulting in extensive ECM denaturation or elimination of structural integrity, would similarly lead to elimination of integrin-ECM interactions and cell death. Thus, integrins perform a biosensory role through the cell's interactions with the surrounding ECM.
This signaling may be particularly important during invasive processes, such as inflammation, angiogenesis, tumorigenesis, metastasis and tissue differentiation or remodeling. During these processes cells often break contact with neighbors and rely upon ECM interactions to sense their surroundings. Clearly, different combinations of extracellular cues are present in these processes and resistance to extrinsic or intrinsic apoptosis pathways may play different roles in the progression of these events. As the mechanistic details of the integrin-mediated and apoptotic signaling pathways become clearer, it should become possible to develop logical combinations of drugs that optimize (or minimize) the susceptibility of selected target cell populations to apoptosis during therapeutic interventions.
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