Download Redox regulation of protein tyrosine phosphatases during receptor

Review
TRENDS in Biochemical Sciences
Vol.28 No.9 September 2003
509
Redox regulation of protein tyrosine
phosphatases during receptor tyrosine
kinase signal transduction
Paola Chiarugi and Paolo Cirri
Dipartimento di Scienze Biochimiche, Università di Firenze, viale Morgagni 50, 50134 Firenze, Italy
In addition to protein phosphorylation, redox-dependent
post-translational modification of proteins is emerging
as a key signaling system that has been conserved
throughout evolution and that influences many aspects
of cellular homeostasis. Both systems exemplify dynamic
regulation of protein function by reversible modification,
which, in turn, regulates many cellular processes such
as cell proliferation, differentiation and apoptosis. In
this article we focus on the interplay between phosphorylation- and redox-dependent signaling at the level
of phosphotyrosine phosphatase-mediated regulation
of receptor tyrosine kinases (RTKs). We propose that
signal transduction by oxygen species through reversible
phosphotyrosine phosphatase inhibition, represents a
widespread and conserved component of the biochemical machinery that is triggered by RTKs.
Activation of receptor tyrosine kinases (RTKs) is implicated in cell proliferation, motility, actin reorganization
and chemotaxis. Tight regulation of RTK signaling is
therefore crucial for eliciting an appropriate type and
level of response to external stimuli. It has been proposed
that protein tyrosine phosphatases (PTPs) negatively
regulate RTK activity and downstream signaling [1].
Recent work on PTPs has demonstrated that these
enzymes undergo reversible inhibition through oxidation
of active-site cysteine residues [2].
Reactive oxygen species in receptor-mediated signal
transduction
During the past decade, reactive oxygen species (ROS),
2
namely H2O2, Oz2
2 and OH , have been identified as
important mediators of cell growth, differentiation and
apoptosis (Fig. 1). Mitochondria are the predominant
source of ROS in all cell types, 1– 5% of electrons from the
respiratory chain being typically diverted to the formation
of Oz2
2 by ubiquinone-dependent reduction [3] (Fig. 1a).
Recent evidence supports the hypothesis that mitochondrial ROS production is not only related to apoptotic cell
death [4] but, in many conditions, assumes an essential
signaling significance, for example, during tumor necrosis
factor-a (TNFa) stimulation [5], hypoxia [6] and integrin
signaling [7].
Corresponding author: Paolo Chiarugi ([email protected]).
In addition to mitochondria, another cellular source of
ROS is NADPH oxidase. This is a multi-protein complex
(originally characterized in leukocytes) that is formed by
membrane (gp91phox and p22phox) and cytosolic (Rac,
p67phox, p47phox and p40phox) proteins [8]. Membrane
oxidases that are similar to the phagocytic NADPHoxidase complex are expressed almost ubiquitously in
non-phagocytic cell types [9]. NADPH oxidase catalyzes
the one-electron reduction of O2 to Oz2
2 , which spontaneously or enzymatically dismutes to H2O2 (Fig. 1b).
Several lines of evidence demonstrate that NADPH
oxidase is specifically involved in the generation of ROS
by soluble growth factors such as transforming growth
factor-b1 [10,11], interleukin-1 [12], TNFa [13], insulin
[14], platelet-derived growth factor (PDGF) [15], epidermal growth factor (EGF) [16], angiotensin II [17],
thrombin and lysophosphatidic acid [18]. Growth-factor
stimulation can induce intracellular ROS production via
the activation of the phosphatidylinositol 3-kinase (PI3K)
pathway, resulting in the activation of the small GTPase
Rac1, which, in turn, stimulates NADPH-oxidase activity
[19]. These findings suggest that ROS formation plays a
role in mitogenic signaling elicited by cytokines and
growth factors.
Finally, growth-factor-stimulated ROS production can
also be generated via a phospholipase A2-dependent
mechanism. Indeed, growth factors activate the phospholipase A2-dependent lipoxygenase in a Rac1-dependent manner [20], which generates Oz2
2 and H2O2 as
by-products.
Therefore, it seems that the small GTPase Rac1 is
central in the regulation of ROS signaling. This assumption is further strengthened by the recent observation that
Rac 1, in addition to its role in NADPH and lipoxygenase
activation, is also involved in mitochondrial oxidant
production [7].
PTPs as intracellular targets of ROS
Recent evidence has claimed a role for H2O2 as an
intracellular messenger that regulates protein phosphorylation of tyrosine residues [15,16]. Unlike other
known second messengers, H2O2 is not directly recognized
by a sensor protein, instead it modulates intracellular
protein phosphorylation by the reversible modification of
downstream effectors. H2O2 is a mild oxidant and might
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Review
510
(a)
TRENDS in Biochemical Sciences
(b)
TNFα
Ceramide
Hypoxia
p53
Apoptosis
Integrin signaling
Serum deprivation
Oncogenic Ras
I
II
Vol.28 No.9 September 2003
Growth factors
Cytokines
Hormones
Immunological stimuli
Oncogenic Ras
Hypoxia/reoxygenation
Cytochrome c
III
IV
UQ/UQ-H2
O2• –
Dismutation
H2O2
NADPH
oxidase
Lipoxygenase
Rac
NADPH
2AA + O2
+ NADP+ + H+ 2O2• –
2HPETE
2O2
Dismutation
H2O2
Ti BS
Fig. 1. Biological stimuli associated with the generation of reactive oxygen species (ROS). The main sources of intracellular ROS are illustrated and the specific stimuli
that elicit the response are listed [57]. (a) The mitochondrial generation of ROS represents a relevant by-product of electron flow through the respiratory chain (complexes
1 –4 are indicated in blue). Oxygen is converted to Oz2
2 by ubiquinone (UQ)-mediated one-electron reduction, which is then converted to H2O2 by spontaneous or enzymaticdismutation that is mediated by superoxide dismutase. Mitochondrial ROS production is itself modulated by a variety of stimuli (listed), and, at least for integrin signaling,
is reported to be Rac dependent [7]. (b) Upon activation, both NADPH oxidase and lypoxygenase (or cycloxygenase) are translocated to the membrane and, therefore, the
small GTPase Rac is activated. Both oxidases produced Oz2
2 , which is then converted to H2O2 by spontaneous or enzymatic-dismutation mediated by superoxide dismutase.
Abbreviations: AA, arachidonic acid; HPETE, hydroperoxyeicosatetraenoaic acid.
oxidize cysteine residues in proteins to cysteine sulfenic
acid or disulfide, both of which are readily re-reduced
to cysteine by various cellular reductants. Proteins with
low-pKa cysteine residues, which are vulnerable to oxidation by H2O2, include transcription factors such as the
nuclear factor k-B [21], activator-protein 1 [22], hypoxiainducible factor [23], p53 [24], the p21Ras family of protooncogenes [25] and, notably, PTPs. All PTPs contain an
essential cysteine residue in the signature active-site motif
Cys-Xaa-Xaa-Xaa-Xaa-Xaa-Arg that exists as a thiolate
anion at neutral pH [26]. This thiolate anion contributes to
the formation of a thiol-phosphate intermediate in the
catalytic mechanism of PTPs. Oxidation of the active-site
cysteine of PTPs to the cysteine sulfenic derivative by
various oxidant agents, including H2O2, leads to enzymatic
inactivation, however, this modification can be reversed by
incubation with thiol compounds [27– 29]. These observations suggest that oxidation of the cysteine residue of
PTPs might occur in vivo in response to ROS or to an
increase in redox potential. Recent work has provided
insight into how PTPs might transduce oxidative stress
conditions. A reversible oxidation was first demonstrated
for PTP1B during EGF [29] and insulin [14] signaling, and
then for low molecular weight-PTP (LMW-PTP) during
PDGF stimulation [30]. Both PTP1B and LMW-PTP fully
rescue their phosphatase activity due to re-reduction
30 min after receptor activation [31,32]. Reversible oxidation of Src-homology 2 domain (SHP-2) PTP following
PDGF stimulation has also been reported [33]. In addition,
Rhee and coworkers have shown intramolecular disulfidebridge-dependent in vitro redox regulation of lipid phosphatase PTEN (phosphatase and tensin homolog) [34].
Savintsky and colleagues have provided evidence for
Cdc25C phosphatase degradation that is triggered by
H2O2-induced disulfide-bond formation between the activesite cysteine and another invariant cysteine residue [35].
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Finally, as detected by fluorescence resonance energy
transfer, H2O2-dependent Cys723 oxidation stabilizes
dimers of transmembrane receptor PTPa (RPTPa), resulting in phosphatase inactivation [36].
RTK activation via redox regulation of PTPs
It is well established that ligand binding to RTKs increases
their intrinsic tyrosine kinase activity [37]. The tyrosine
phosphorylation level of an RTK is given by the ratio
between its intrinsic tyrosine kinase activity and the
coordinated activity of PTPs (see Table 1 for an outlook of
PTPs identified as negative regulators of RTKs). Growing
evidence suggests that inhibition of PTP activity, as well as
reduced sensitivity of RTKs to dephosphorylation [38],
occurs after RTK dimerization and, thereby, also contributes to the ligand-induced increase in RTK tyrosine
phosphorylation [1]. Here, we focus on the emerging hypothesis that the transient negative regulation of PTPs – due
to oxidants produced in response to RTK-ligand stimulation – represents a strategy that has been adopted
by cells to promote RTK signaling by avoiding its
prompt inactivation by PTPs. The functional relevance
of ROS-mediated PTP inhibition in growth factor signaling
has been demonstrated by blocking their accumulation.
First, Sundaresan provided the initial piece of evidence by
demonstrating that the overexpression of catalase in
vascular smooth muscle cells blocked PDGF receptor
(PDGF-R)-induced tyrosine phosphorylation of extracellular signal-regulated kinase (ERK), as well as PDGFinduced DNA synthesis and migration [15]. Second, interference with H2O2 production through catalase loading of
A431 cells dramatically reduced tyrosine phosphorylation
of EGF receptor (EGF-R) [16]. Third, catalase pretreatment abolished both the insulin-stimulated production of
ROS and the inhibition of PTP1B, and was associated with
reduced tyrosine phosphorylation of insulin receptor [14].
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Vol.28 No.9 September 2003
Table 1. Protein tyrosine phosphatases (PTPs) identified as negative regulators of receptor tyrosine kinases (RTKs): the investigation
method and the documented redox regulation for every RTK/PTP couple was indicateda
PTPs
RTKs
Investigation method
Redox regulation
Refs
LMW-PTP
PDGF-R
Expression of dominant negative mutant/
co-immunoprecipitation
Two hybrid system
Expression of dominant negative mutant/
co-immunoprecipitation
Mouse gene knockout
Expression of dominant negative mutant
Overexpression
Overexpression
Expression of dominant negative mutant
Overexpression/co-immunoprecipitation
Mice with natural gene mutation
Mice with natural gene mutation
Yes
[30,58]
Not yet
Not yet
[59]
[60]
Yes
Yes
Not yet
Not yet
Not yet
Not yet
Not yet
Not yet
In vitro
Yes
Not yet
[14,61]
[16,62]
[63]
[42]
[64]
[65]
[66]
[67]
[27]
[68]
[69]
Not yet
Not yet
Not yet
Not yet
In vitro
Not yet
Reported for exogenous oxidative stress
Not yet
Not yet
[70]
[71]
[71]
[72]
[28]
[73]
[36]
[74]
[73]
VEGF-R2
Insulin-R
PTP1B
DEP-1
SHP-1
SHP-2
T cell PTP
LAR
RPTPa
RPTPs
RPTPe
Insulin-R
EGF-R
IGF1-R
PDGF-R
PDGF-R
EGF-R
CSF-1
Ros
–
PDGF-R
EGF-R
EGF-R
HGF-R
Insulin-R
–
Insulin-R
–
EGF-R
Insulin-R
In vitro dephosphorylation, association
Expression of dominant negative mutant/
co-immunoprecipitation
Expression of dominant negative mutant
Antisense oligonucleotides
Antisense oligonucleotides
Antisense oligonucleotides
Overexpression
Antisense oligonucleotides/overexpression
Overexpression
a
Abbreviations: CSF-1, colony-stimulating factor-1; DEP-1, density enhanced phosphatase-1; EGF, epidermal growth factor; EGF-R, EGF receptor; HGF-R, hepatocyte growth
factor receptor; IGF-R, insulin-like growth factor receptor; insulin-R, insulin receptor; LAR, leukocyte-associated receptor; LMW-PTP, low molecular weight protein tyrosine
phosphatase; PDGF-R, platelet-derived growth factor receptor; PTP, protein tyrosine phosphatase; RPTP, receptor-PTP; SHP, Src homology phosphatase; VEGF-R2, vascular
endothelial growth factor receptor-2.
Finally, blocking ROS production in PDGF-stimulated
cells, either achieved by catalase pretreatment or inhibition of the NADPH oxidase by diphenyl iodide, led to the
reduction of PDGF-R tyrosine phosphorylation [39]. In
addition, during PDGF stimulation the kinetics of ROS
production, PTP redox inhibition and receptor phosphorylation displayed an excellent alignment, suggesting a strict
temporal correlation among these events [39]. Hence, it
is likely that the redox inhibition of PTPs has an important role in RTK signaling, and that the rescue (via
re-reduction) of the PTP catalytic activity after oxidation
is followed by a dephosphorylation of activated receptor,
thereby terminating the signal elicited from the receptor.
Thus, the ROS produced after RTK engagement might be
considered as intracellular second messengers that are
involved in the signal-transduction machinery of soluble
hormones. These second messengers form a feedback loop
that, through the inhibition of PTPs, upregulates RTK
tyrosine phosphorylation and, ultimately, leads to their
own activation (Fig. 2).
Although many PTPs can interact with more than one
RTK and vice versa, PTP modulation of RTKs can offer
different levels of specificity. We can speculate that celland tissue-specific expression of PTPs and RTKs provide
the first level of selectivity. A possible second level of
selectivity is provided by substrate specificity through siteselective dephosphorylation of RTK-specific tyrosine(s) by
PTPs. Indeed, RTK signaling can be affected by general
dephosphorylation, including dephosphorylation of regulatory phosphotyrosines, or by dephosphorylation of binding
sites for downstream signaling molecules. The effects might
be very different: dephosphorylation of the RTK regulatory
http://tibs.trends.com
RTK ligand
NADPH
oxidase
P
P
Rac
P RTK P
P
ROS
P
SH
PTP
Downstream
signaling
Reduced/
active
PTP
SOH
Oxidated/
inactive
Reducing agents
Ti BS
Fig. 2. Reactive oxygen species (ROS) as modulators of receptor tyrosine kinase
(RTK) tyrosine phosphorylation. Ligand-induced activation of RTKs leads to the
phosphatidyl inositol 3-kinase (PI3K)-mediated activation of Rac, which, in turn,
switches on the production of ROS from NADPH oxidase. Among intracellular
ROS targets are protein tyrosine phosphatases (PTPs), which are catalytically
inactivated by oxidation, hence allowing the sustained RTK phosphorylation or
activation required for cell-proliferation induction. The subsequent decrease of
intracellular ROS concentration is accompanied by the recovery of PTP enzymatic
activity (with a re-reduction mechanism that is not well defined). Full re-activated
PTPs leads to RTK dephosphorylation and to the termination of the signal.
512
Review
TRENDS in Biochemical Sciences
tyrosines leads to subsequent termination of the signal,
whereas site-specific dephosphorylation modulates single
signal-transduction pathways. Dephosphorylation of the
kinase-activation residues has been reported for LMW-PTP
on PDGF-R Tyr857 [40] and for PTP1B on the insulin
receptor [41]. By contrast, site-specific dephosphorylation
of specific RTK tyrosines has been reported for densityenhanced phosphatase-1 (DEP-1), which displays siteselectivity dephosphorylation of PDGF-R, preferring
Tyr763, Tyr771 and Tyr778 [42], and for SHP2, which
reveals preferential dephosphorylation of Tyr771, Tyr751
and Tyr750 of PDGF-R [43]. In this scenario, we hypothesize that a third level of selectivity on PTP modulation
of RTK signaling could come from different sensivity of
PTPs to ROS-mediated inactivation, owing to possible
differences in pKa values of target cysteine residues,
and/or differences in the ability to rescue the enzymatic
activity after re-reduction. Although great differences
have been reported in the pKa values of catalytic cysteine
residues among PTPs [44], the real differential vulnerability of PTPs to oxidation by H2O2 remains to be
addressed. This discriminating regulation of PTPs, together
with other post-translational modifications affecting PTP
enzymatic activity, might cause specific responses in RTK
signal transduction.
Intriguing findings suggest that redox regulation of
PTPs might be of pathophysiological significance. For
example, recent reports have shown reduced basalinduced and growth-factor-induced ROS production in
conditions of cell-growth inhibition [45,46]. Thus, antiproliferative conditions might shift the redox equilibrium
of PTPs towards the reduced state, which would favor
PTP activity and ensure silencing of RTK-dependent
mitogenic signaling. Conversely, the constitutive high
levels of H2O2 that are found in tumor cells [47,48] might
cause oxidation-dependent PTP inactivation and a subsequent increase in RTK-mediated cell proliferation.
These findings might be of pathogenetic relevance to
oncogenic transformation and tumor progression.
The role of redox regulation of PTPs in the
ligand-independent activation of RTKs
A large body of experimental evidence suggests that, in
addition to endogenous ROS formation, extracellular
oxidants affect RTK signaling. Adverse agents such as
radiation, exposure to metals, alkylating agents and
environmental oxidants have been found to activate
RTKs in a ligand-independent manner, which is referred
to as RTK trans-activation [49]. Again, oxidation and
subsequent inactivation of PTPs seems responsible for
RTK trans-activation by extracellular oxidants. For
instance, cysteine modification in the PTP catalytic site
has been proposed for both UV- and alkylating agentinduced RTK trans-activation [50,51], thus confirming a
key role for PTP inhibition in the control of RTK tyrosine
phosphorylation, even in the absence of the natural ligand.
Moreover, in phagocytes and lymphocytes, NADPH oxidase produces oxidants involved in host defense and
inflammation that might result in pro-oxidant conditions
for bystander cells [8]. It is an intriguing possibility that
the pro-oxidant environment causes redox-regulation of
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Vol.28 No.9 September 2003
RTKs (through PTP inhibition) in neighboring cells during
inflammation, but it has not been demonstrated. If this
interpretation is proven, it could shed a new light on cell
signaling during the inflammatory reaction and have
important pathophysiological and therapeutic implications.
Stimulation of G-protein-coupled receptors (GPCRs)
and activation of cell-adhesion receptors can also lead to
RTK trans-activation. Although an extracellular pathway
has been proposed for EGF-R trans-activation via a metalloprotease-dependent cleavage of heparin-binding EGF
[52], the involvement of ROS has been proposed as a
causal event for intracellular GPCR-mediated RTK transactivation [2,53,54]. Interestingly, activation of different
GPCRs leads to the generation of H2O2, which suggests
that subsequent PTP inactivation can contribute to intracellular GPCR-induced trans-activation of RTKs. Indeed,
the prevention of H2O2 accumulation by antioxidants
blocks RTK stimulation and ERK activation in cells
treated with lysophosphatidic acid (LPA), angiotensin II,
or serotonin, thereby suggesting a role for PTP redox
inhibition in the intracellular RTK trans-activation pathways starting from these GPCRs [53,55,56].
Concluding remarks
Mounting evidence indicates PTP redox regulation as
pivotal in RTK signaling. Indeed, although growth-factorinduced oxidative PTP inactivation enables correct duration and amplitude of RTK signal transduction, the
transient nature of oxidation-dependent PTP inhibition
warrants RTK dephosphorylation and signal downregulation. Hence, given the remarkable importance of PTP in
cell proliferation and related pathophysiology, further
studies are needed to define the complete set of redoxregulated PTPs during RTK signaling, their differential
sensivity to oxidants and the ways in which their oxidation
is reversed.
Acknowledgements
We thank G. Ramponi and G. Camici for helpful suggestions regarding
cellular redox regulation, and A. Chiarugi for critical reading of the
article. Work in authors’ laboratories has been supported by grants from
the Italian Association for Cancer Research, Ministero della Università e
Ricerca Scientifica e Tecnologica and Cassa di Risparmio di Firenze.
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