The insulin receptor IR is a trans-membrane tyrosine kinase that becomes activated upon ligand binding.. Keywords: diabetes; insulin receptor; protein tyrosine phos-phatase; knockout mic
Trang 1M I N I R E V I E W
Coordinated action of protein tyrosine phosphatases
in insulin signal transduction
Alan Cheng, Nadia Dube´, Feng Gu and Michel L Tremblay
Department of Biochemistry and McGill Cancer Center, McGill University, Montreal, Quebec, Canada
Insulin is the principal regulatory hormone involved in the
tight regulation of fuel metabolism In response to blood
glucose levels, it is secreted by the b cells of the pancreas and
exerts its effects by binding to cell surface receptors that are
present on virtually all cell types and tissues In humans,
perturbations in insulin function and/or secretion lead to
diabetes mellitus, a severe disorder primarily characterized
by an inability to maintain blood glucose homeostasis
Furthermore, it is estimated that 90–95% of diabetic patients
exhibit resistance to insulin action Thus an understanding of
insulin signal transduction and insulin resistance at the
molecular level is crucial to the understanding of the
patho-genesis of this disease The insulin receptor (IR) is a
trans-membrane tyrosine kinase that becomes activated upon
ligand binding Consequently, the receptor and its
down-stream substrates become tyrosine phosphorylated This activates a series of intracellular signaling cascades which coordinately initiate the appropriate biological response One important mechanism by which insulin signaling is regulated involves the protein tyrosine phosphatases (PTPs), which may either act on the IR itself and/or its substrates Two well characterized examples include leuckocyte antigen related (LAR) and protein tyrosine phosphatase-1B (PTP-1B) The present review will discuss the current knowledge of these two and other potential PTPs involved in the insulin signaling pathway
Keywords: diabetes; insulin receptor; protein tyrosine phos-phatase; knockout mice; signaling
I N T R O D U C T I O N
Insulin is the most potent anabolic hormone identified to
date It is produced and secreted in a regulated fashion by
the b cells in the pancreatic islet Practically all cell types are
responsive to insulin, although the term Ôinsulin sensitive
tissuesÕ often refer to the liver, muscle and adipose The
primary biological effect of insulin is to maintain glucose
homeostasis It acutely promotes glucose uptake in muscle
and adipose tissue, while suppressing hepatic glucose
production However, insulin also stimulates lipogenesis,
protein synthesis, and has been shown to be a mitogen for
certain cell types
The importance of insulin function is highlighted by its
disregulation in diabetes mellitus, a human disease
charac-terized by an impairment in insulin secretion (type I; insulin
dependent) and/or action (type II; noninsulin dependent)
Currently, diabetes is recognized as the world’s most
common metabolic disorder, affecting people globally and
of all age groups For the year 2000, it was estimated that
over 175 million people worldwide, were afflicted with this
disease (International Diabetes Institute, World Health Organisation) Clinically, diabetes is primarily characterized
by fasting hyperglycemia, is often associated with cardio-vascular risk factors, and may lead to severe complications
At present, type I diabetes comprises about 5–10% of all diagnosed cases The molecular complexity of this disorder
is well documented, and current therapies revolve around exogenous insulin supplementation [1,2] On the other hand, type II diabetes accounts for the remaining 90–95% of the cases At the molecular level, a postreceptor defect of insulin signaling is mainly thought to underlie the basis of insulin resistance in type II diabetes [3] Consequently, understand-ing the mechanisms by which this may occur will provide invaluable insight for the development of novel therapies In the present review, we will summarize the current under-standing of insulin signaling with particular focus on how protein tyrosine phosphatases regulate this process
B R I E F O V E R V I E W O F I N S U L I N
S I G N A L I N G Insulin is a pleiotropic hormone with multiple integrated signaling pathways For brevity, we will only describe those relevant to this review The insulin receptor (IR) belongs to a subclass of the large family of protein tyrosine kinases [4] It
is a transmembrane protein comprising two extracellular
a subunits and two transmembrane b subunits (Fig 1) Upon binding to insulin, the intrinsic kinase activity of the receptor is increased, and the IR undergoes autophospho-rylation on several tyrosine residues located on the cyto-plasmic portion of the b subunits [5] Subsequently, these phosphotyrosine residues, in their surrounding sequence
Correspondence to M L Tremblay, Department of Biochemistry
and McGill Cancer Center, McGill University, 3655 Promenade
Sir William Osler, Room 715, Montreal, Quebec, Canada, H3G 1Y6.
Fax: + 1 514 398 6769, Tel.: + 1 514 398 7290,
E-mail: tremblay@med.mcgill.ca
Abbreviations: GLUT4, glucose transporter 4; IR, insulin receptor;
IRS, insulin receptor substrate; PTP, protein tyrosine phosphatase;
SH2, Src homology 2; PI3-kinase, phosphatidyl inositol 3-kinase.
(Received 6 August 2001, accepted 20 September 2001)
Trang 2context, recruit signaling molecules containing SH2 (Src
homology 2) or PTB (phosphotyrosine binding) domains
[6] Although not limited to, most of the recruited proteins
belong to a class of adapter proteins of the insulin receptor
substrate (IRS) family [7,8] The best characterized examples
include Shc, which is primarily involved in the activation of
the mitogen activated protein kinase (MAPK) pathway for
mitogenic effect; and IRS-1, which can transmit insulin
signaling to both metabolic and mitogenic processes [9,10]
The primary function of insulin is to maintain glucose
homeostasis For most cells, this is achieved via the insulin
dependent translocation of the glucose transporter,
GLUT4, from intracellular vesicles to the cell surface [11–
13] Upon recruitment of IRS-1 to the activated IR, IRS-1
becomes heavily tyrosine phosphorylated and serves as a
large scaffolding protein by binding to several SH2
containing proteins The most prominent example is the
p85 regulatory subunit of phosphatidylinositol 3-kinase
(PI3-kinase) Binding to p85 recruits the p110 catalytic
subunit of kinase, resulting in the activation of the
PI3-kinase pathway, a necessary component involved in
GLUT4 translocation However, activation of PI3-kinase
alone is insufficient, as platelet-derived growth factor which
also activates PI3-kinase, does not promote glucose
trans-port [14,15] In fact, recent studies in 3T3-L1 adipocytes
have demonstrated a pathway parallel to PI3-kinase, which
is required for insulin-mediated GLUT4 translocation
Activation of the IR results in the formation of a protein
complex involving the scaffolding proteins CAP and Cbl
Subsequent tyrosine phosphorylation of Cbl by the IR leads
to translocation of the Cbl–CAP complex to lipid rafts, a
process that is necessary for GLUT4 translocation [14,15]
In contrast to the activation and propagation of insulin
signal transduction, the negative regulatory components
that attenuate insulin signaling are less well defined Because
tyrosine phosphorylation of the IR correlates with its
activity and function, the protein tyrosine phosphatases [16]
are prominent candidates to negatively regulate insulin
action Indeed, vanadium compounds, known inhibitors of
PTPs, have long been known to possess insulin mimetic or
enhancing effects [17–19] However, it should also be noted that there is evidence for serine phosphorylation [5] and O-glycosylation [20] in attenuating insulin signaling, but these will not be discussed here
T H E P R O T E I N T Y R O S I N E
P H O S P H A T A S E F A M I L Y PTPs represent a large family of enzymes that rival the PTKs in both functional and structural diversity Members
of this group can be classified into receptor vs nonreceptor PTPs Common to all members is a highly conserved core of about 250 amino acids that make up the catalytic domain The PTP signature motif, V/IHCSAGXGRXG sequence contains an invariant cysteine residue that is critical for PTP activity [21] In addition, some receptor PTPs (rPTPs) possess two such domains, although only one is usually active [22–24] Apart from the catalytic domain, the rest of the protein is quite divergent amongst PTPs For the sake of simplicity, and to illustrate the point, we will only depict several PTPs relevant to insulin signaling (Fig 2)
A subset of rPTPs contain structural motifs such as immunoglobulin-like and fibronectin type III elements These structures have been found in cell-adhesion molecules and suggest a role for these PTPs in cell–cell contact or cell– extracellular matrix interactions On the other hand, all intracellular PTPs possess a single conserved phosphatase domain, that is flanked at either the N- or C-terminus by noncatalytic segments These segments play regulatory roles, either by binding each PTP to its substrate(s) or to adapter molecules through domains that regulate protein– protein interactions, by targeting the PTP to a particular subcellular compartment, or by keeping the enzyme in an inactive conformation
To elucidate the function of PTPs and their mechanisms
of action, identification of their substrates is critical Over the past decade, many studies on PTPs have utilized a strategy called Ôsubstrate trappingÕ [25] In this method, mutagenesis of the conserved cysteine to serine (CfiS) or an aspartate to alanine (DfiA) within the catalytic domain of
Fig 1 Scheme of the major insulin signaling
pathways The activated insulin receptor
phosphorylates tyrosine residues on IRS
pro-teins, Shc, CAP and other intracellular
sub-strates These substrates then bind to various
downstream signaling effectors, transmitting
the metabolic and mitogenic signal of insulin.
CAP, c-Cbl-associating protein; FRAP/
mTOR, mammalian target of rapamycin;
MAP, mitogen activated protein; MAPK,
MAP kinase, MEK, MAP/ERK kinase;
PI3-kinase, phosphatidylinositol 3-kinase; PKB/
Akt, protein kinase B; SHP-2, SH2 containing
phosphatase-2; Sos, Son of sevenless Refer to
text for more details.
Trang 3PTPs eliminates their enzymatic activity However the
resulting mutated enzymes are still able to recognize their
specific targets with complete loss of or reduced ability to
catalyze the removal of the phosphate moiety from tyrosine
Thus, these Ôtrapping mutantsÕ provide a convenient means
to isolate potential substrates of PTPs in a rapid and
efficient way In a modified approach, this trapping strategy
was used in combination with gene targeting technology to
identify physiological substrates of PTPs [26]
C A N D I D A T E I R P T P s
As a first step to identify PTPs that play a regulatory role in
insulin signaling pathway, several groups studied the
expression profile of PTPs expressed in the major insulin
sensitive tissues For example, rPTPa, LAR, SHP-2 and
PTP-1B have been identified as the four major PTPs in rat
adipocytes [27] Moreover, immunodepletion studies in rat
skeletal muscle demonstrated that LAR, SHP-2 and
PTP-1B were the three major enzymes responsible for PTP
activity [28] Further compelling evidence for these PTPs in
insulin signaling stems from the fact that the expression
levels and/or activity these specific PTPs are increased in
insulin resistant obese patients [29]
L A R
LAR belongs to a subfamily of rPTPs that also include
PTPr and PTPd Members of this subfamily are expressed
as preproteins and undergo proteolytic processing to
generate a molecule containing two cytoplasmic catalytic
domains linked through a single hydrophobic
transmem-brane stretch to a large extracellular segment (Fig 2) An
additional proteolytic cleavage site near the transmembrane
stretch allows shedding of the extracellular domain, and
has been suggested to be a mechanism controlling LAR
function [30,31] The extracellular segment consists of three
immunoglobulin-like repeats and four to eight type-III
fibronectin repeats On the cell surface the two subunits of
LAR form a complex of two noncovalently associated
subunits [32,33]
The localization of this rPTP makes it a logical candidate
for dephosphorylation of the IR Indeed, an association
between LAR and the IR has been demonstrated by
coimmunoprecipitaition studies in cells [34] Furthermore,
these studies also showed that insulin treatment increased the amount of IR/LAR complex detected Consistent with these results, overexpression or antisense suppression stud-ies of LAR showed that this rPTP could negatively regulate
IR, IRS-1 and Shc phosphorylation, as well as the PI3-kinase and MAPK pathways [35–37] In CHO-hIR cells expression of LAR reduced insulin stimulated tyrosine phosphorylation of IR and IRS-1, as well as DNA synthesis [38] Importantly, proper membrane localization of LAR seems to be required, as expression of the cytoplasmic domain of LAR alone does not recapitulate these effects Studies with knockout mice indicate that, although LAR
is not required for embryonic development, it seems to be necessary for mammary gland development [39] The effect
of LAR deficiency on insulin signaling has yet to be reported in these mice Using a different strategy, Skarnes
et al generated transgenic mice expressing reduced (near undetectable) levels of LAR transcript [40,41] Studies in this model were performed to provide some in vivo evidence that LAR is involved in glucose homeostasis and insulin signaling [42] However, insulin stimulated receptor phos-phorylation and basal PI3-kinase activity were only modestly increased under reduced LAR expression Further-more, IRS-1 tyrosine phosphorylation was unaffected
In contrast, insulin stimulated PI3-kinase activity was diminished in these mice compared to controls It should
be noted that the importance of LAR for proper neuronal development [41,43] makes the situation a complex one
To overcome the physiological complexity of LAR, transgenic mice overexpressing this rPTP in skeletal muscle (MCK-hLAR mice) were developed [44] Importantly, this model was intended to approximate the increased expres-sion of LAR in insulin-resistant humans MCK-hLAR mice maintain glucose levels at higher plasma insulin levels, and glucose uptake is reduced in skeletal muscles, compared to controls In muscle tissue of these mice, insulin induced IR and IRS-1 phosphorylation is normal, but IRS-2 phos-phorylation is decreased Although IRS-1 can be dephos-phorylated by LAR in vitro [45], studies on IRS-2 have yet
to be performed Furthermore, IRS-1 or IRS-2 associated PI3-kinase activity was also diminished Taken together, these results suggest that LAR negatively regulates insulin signaling primarily through dephosphorylation of IRS-2 (or other IRS proteins), although IR and IRS-1 may be affected
in other tissues or physiological states Finally,
MCK-Fig 2 The prominent protein tyrosine phos-phatases implicated in insulin signal transduc-tion Structure of several phosphatases implicated in insulin signal transduction rPTP-a, LAR, PTP-1B and SHP-2 are the major phosphatases acting on the insulin signaling pathway rPTP-e, rPTP-r and TC-PTP are candidates shown by in vitro binding and dephosphorylation assays or suggested by their structure similarity to phosphatases involved in the insulin signaling pathway.
Trang 4hLAR mice also provide an important model to understand
the role of LAR in the pathogenesis of insulin resistance
R P T P a
rPTPa mRNA is expressed in most tissues, with highest
expression in brain and kidney, suggesting that this PTP
could play a fundamental role in the physiology of all cells
[46] The best-characterized substrate of rPTPa is the Src
kinase, with particular emphasis in the context of
transfor-mation and neuronal differentiation [47,48] In addition,
p130Cas [49] and the IR [50] have also been shown to be
potential substrates of rPTPa Expression of rPTPa in cells
can inhibit some of insulin mediated effects For example,
expression of rPTPa in BHK-IR cells inhibits
insulin-mediated cell rounding and growth inhibition of those cells,
concomitant with increased IR phosphorylation [51]
Fur-thermore, in rat adipocytes, rPTPa decreases insulin
stimu-lated GLUT4 cell surface translocation [52] In contrast,
antisense studies in 3T3-L1 adipocytes showed that rPTPa
was dispensable for insulin induced MAPK activation and
DNA synthesis [53] Although mice deficient in rPTPa have
demonstrated the importance of this PTP in the activation
of Src kinases [54,55], its physiological importance in insulin
signaling remains unclear
S H P - 2
SHP-2 [56] is a widely expressed nonreceptor PTP that
contains two N-terminal SH2 domains, a C-terminal
catalytic domain and a C-terminal segment containing
two tyrosyl phosphorylation sites (Fig 2) The SH2
domains of SHP-2 bind many activated growth factor
receptors as well as IRS-1 [57–59] It has been suggested that
these associations displace intramolecular interactions of
SHP-2, leading to a conformationally more open state and
increased catalytic activity [60–62] In contrast to many
other growth factor receptor associated PTPs, SHP-2 does
not seem to dephosphorylate the receptor In fact, genetic
studies indicate that SHP-2 is a positive effector of growth
factor receptor signaling [63] However, Kuhne et al [64]
proposed that the binding of IRS-1 to SHP-2 enhances its
phosphatase activity toward IRS-1, resulting in its
dep-hosphorylation in vivo Thus SHP-2, in contrast with most
other PTPs, may act as either a positive or negative
regulator of growth factor signaling
Many studies suggest that SHP-2 binds to both the IR and
IRS-1 For example, the IR and SHP-2 interact in a yeast
two-hybrid assay [65] Transfection experiments demonstrated
that this association is mediated between the proximal SH2
domain of SHP-2 and phosphotyrosine 1146 of the activated
insulin receptor [66] Insulin also induces the formation of a
complex of IRS-1 and SHP-2, requiring the tyrosines 1172
and 1222 of IRS-1 [59,67] However, others have suggested
that SHP-2 is not the major protein complexed with IRS-1 in
insulin stimulated 3T3-L1 adipocytes [68]
Microinjection of interfering molecules [69],
overexpres-sion of dominant negative mutants [70–72], and genetic
studies [63] indicate that SHP-2 is required for activation of
the MAPK pathway by a variety of growth factors,
including insulin However, the requirement for SHP-2
binding to IRS-1 for this pathway is unclear [69,73] SHP-2
can also bind to IRS-2, IRS-3 [74] and IRS-4, suggesting
possible functional redundancy for the SHP-2/IRS-1 association In addition, SHP-2 binding to SHPS-1 [SH2-domain bearing protein tyrosine phosphatase (SHP) sub-strate-1] [75] may provide an additional pathway for insulin induced MAPK activation In insulin-induced metabolic signaling, a SHP-2 C-S mutant slightly impaired GLUT4 translocation in primary adipocytes, whereas wild-type SHP-2 did not [76]
Genetic studies in mice indicate that SHP-2 is required for embryonic development [77,78] SHP-2 heterozygous knockout mice are viable, and in these mice, plasma insulin and glucose uptake were normal [78] Moreover tyrosine phosphorylation of IR and IRS-1 from muscle tissue was similar to that of wild-type controls These results suggest that SHP-2 may play a minor role in the metabolic effects of insulin that may not be detectable unless SHP-2 function is completely removed Perhaps tissue specific knockouts of SHP-2 can further address the issue
In another approach, the transgenic expression of a mutant SHP-2 was studied [79] This mutant (DeltaPTP) contains the two SH2 domains but lacks the PTP domain and the C-terminal tyrosines In DeltaPTP mice, insulin induced association of endogenous SHP-2 with IRS-1 was reduced, suggesting a dominant negative effect of the mutant SHP-2 protein Furthermore, DeltaPTP mice are insulin resistant, and insulin-mediated tyrosine phosphorylation of IRS-1, stimulation of PI3-kinase and Akt activities were attenuated
in muscle and liver Thus, the inhibition of endogenous SHP-2 by these dominant negative studies suggests a positive role for SHP-2 in insulin-induced metabolic signaling Because DeltaPTP mice are viable, it suggests that the SH2 domains of SHP-2 alone, are able to mediate aspects of signaling required for embryonic development
P T P - 1 B PTP-1B was the first mammalian PTP identified and purified to homogeneity [80] This phosphatase is widely expressed and localizes predominantly to the ER through a cleavable proline-rich C-terminal segment (Fig 2) [81,82] Moreover, the C-terminal 35 amino acids of PTP-1B were found both necessary and sufficient for its targeting to the
ER [81] Cleavage of this segment appears to release the enzyme from the ER and increase its specific activity [83] By
in situ hybridization, Brown-Shimer et al [84] identified PTP-1B as a single-copy gene that mapped to the long arm
of human chromosome 20 in the region q13.1–q13.2 Interestingly this region was identified as a quantitative trait locus linked to obesity and insulin [85]
Studies using the CfiS mutant of PTP-1B (PTP-1B C215S) have demonstrated an association of PTP-1B with the IR [86,87] Upon insulin treatment, PTP-1B becomes tyrosine phosphorylated at three sites (Tyr 66, 152, 153), and mutation of any of these residues impairs its association with the activated IR [87] Within the IR, the binding occurs
in a region containing residues 1142–1153 [88], and muta-tion of tyrosines 1146, 1150, and 1151 diminish the association [87,89] Indeed, crystal structure and kinetic studies provide evidence that PTP-1B preferentially dep-hosphorylates tyrosines 1150 and 1151 of the IR [90]
In addition to the IR, IRS-1 might also be a substrate of PTP-1B [45] Furthermore, in the presence of Grb2, IRS-1 dephosphorylation by PTP-1B is accelerated Thus, these
Trang 5results suggest that PTP-1B could negatively regulate insulin
signaling by acting on two different components of the
pathway
A plethora of studies demonstrate that PTP-1B can
attenuate insulin signaling Microinjection of homogeneous
preparations of PTP-1B protein into Xenopus oocytes
decreases tyrosine phosphorylation of proteins
correspond-ing to the molecular mass of the IR Correspondcorrespond-ingly,
insulin-induced S6 kinase activity and meiotic cell division
were retarded as well [91,92] In mammalian cells, osmotic
loading of PTP-1B antibodies decreases insulin induced
IRS-1 phosphorylation, PI3-kinase activity, as well as DNA
synthesis [93] Finally, overexpression of PTP-1B reduces
glucose uptake and GLUT4 translocation to the cell
membrane [76,94]
Regulation of insulin signaling by PTP-1B appears to be
tissue specific Overexpression of PTP-1B in 3T3-L1
adipo-cytes attenuates insulin induced IR, IRS-1 phosphorylation,
as well as PI3-kinase and MAPK activation [95] However,
neither Akt activation nor glucose transport seemed to be
affected Thus, it is possible that PTP-1B may regulate
insulin-mediated mitogenic, as opposed to metabolic events
in this cell type In contrast, overexpression of PTP-1B in L6
myocytes and Fao hepatoma cells attenuated
insulin-induced Akt activation and glycogen synthesis [96]
An increasing amount of evidence suggests that insulin
signaling can inhibit PTP-1B activity, perhaps as part of a
negative feedback loop For example, insulin stimulation of
3T3-L1 adipocytes induces a burst of intracellular hydrogen
peroxide that is thought to reversibly oxidize and thus
inactivate the invariant cysteine in the catalytic domain of
PTP-1B [97] In another study, it was suggested that insulin
could also down-regulate PTP-1B activity by suppressing
serine phosphorylation and activation on the phosphatase
via an unidentified mechanism [98]
Knockout studies in mice provided in vivo confirmation
that PTP-1B is a bona fide phosphatase of the IR [99,100]
Despite its involvement in a variety of signaling processes,
PTP-1B is surprisingly not required for embryonic
devel-opment, and PTP-1B-deficient mice grow and develop
normally with similar lifespans to wild-type littermates
However, PTP-1B-deficient mice display increased insulin
induced IR phosphorylation in liver and muscle but not
adipose tissue IRS-1 phosphorylation was also increased in
muscle, but it is unclear whether this is because IRS-1 is a
substrate of PTP-1B, or an increased IR activity in
knockout mice Furthermore, PTP-1B-deficient mice are
hypersensitive as assayed by oral glucose tolerance tests,
intraperitoneal insulin tolerance tests, and blood levels of
glucose and insulin
Importantly, PTP-1B-deficient mice remained insulin
sensitive when fed a high fat diet Strikingly, though, they
were also resistant to obesity, due in part to a decrease in fat
cell mass and increased energy expenditure These results
suggest that PTP-1B is a major modulator of insulin
sensitivity and fuel metabolism, and point to PTP-1B as a
potential therapeutic target for the treatment of type II
diabetes and obesity Importantly the insulin receptor
phosphorylation appears to be modified in liver and muscle
tissues but not in adipose tissue, suggesting that although
PTP-1B is a major modulator of the IR, other PTPs may
have tissue specific preferences for the insulin receptor, in
particular in adipocytes
O T H E R C A N D I D A T E P T P s RPTPr
Evidence for a functional role of rPTPr in insulin signaling has not been reported to date However, its similarity with LAR, and the fact that it is expressed in relatively high levels
in insulin sensitive tissues (higher than LAR) [101] make rPTPr a possible candidate to regulate insulin signaling Genetic studies with rPTPr deficient mice reveal the presence of primarily neuroendocrine defects [102,103] However, preliminary studies also indicate that rPTPr deficiency leads to insulin hypersensitivity from measure-ments of fasting glucose and insulin levels (X Elchebly &
M L Tremblay, unpublished observations) As in the case with the LAR knockout it cannot be ruled out that the effects on insulin signaling are secondary to the neuroendo-crine status Thus generation of transgenic lines over-expressing this PTP or the creation of tissue specific knockouts should answer this question
rPTPe rPTPe is similar in structure to rPTPa In addition to rPTPa, expression of rPTPe in BHK-IR cells also inhibits insulin mediated cell rounding and growth inhibition of BHK-IR cells, and requires membrane localization of the PTP [51,104]
TC-PTP, rPTPd and Sap-1
In an attempt to further extend the list of candidate IR PTPs, a mass screen approach utilizing in vitro binding and dephosphorylation assays were performed on a large list of PTPs [105] In this study, in addition to PTP-1B, three other PTPs were suggested to be important for IR dephosphory-lation: TC-PTP, rPTPd and Sap-1 Although not all PTPs tested performed well in these assays, one must consider that for each PTP, their physiological situation is unique and several other factors are implicated For example, these may include: tissue distribution, subcellular localization, as well
as the significance of additional binding partners to form functional multiprotein complexes
C O M P A R T M E N T A L I Z A T I O N
O F I R A N D P T P s
An increasing amount of evidence suggests that regulation
of insulin signaling by PTPs may also occur at the level of compartmentalization In the absence of ligand, the IR normally resides at the plasma membrane Upon insulin binding, the ligand–receptor complex is rapidly sequestered from the plasma membrane and internalized into endo-somes within several minutes [106,107] Here, the acidic pH
of endosomes induces the dissociation of insulin from IR and allows the degradation of insulin by endosomal acidic insulinase [108] The IR is then recycled back to the cell surface However, under conditions of prolonged stimula-tion with saturating levels of insulin, a subset of the IRs are transported to the late endosome and lysosome for degra-dation [109,110]
Although the IR kinase activity is required for ligand-stimulated IR internalization, the role of IR internalization
Trang 6on insulin receptor signaling remains unclear The
endoso-mally associated IRs have been reported to exhibit a
transient elevation of the tyrosine phosphorylation and to
achieve the full activation of the receptor itself as well as the
activation of IRS-1 and PI3-kinase (reviewed in [111]) In
contrast, studies using a dominant negative dynamin
molecule that blocks IR internalization showed that the
inhibition of IR endocytosis had no major effect on IR
autophosphorylation and IRS-1 tyrosine phosphorylation
[112] Even though a 50% decrease in the insulin activated
PI3-kinase activity was observed when IR internalization is
blocked, it did not affect the subsequent Akt
phosphory-lation and activation The only major defect caused by
inhibition of IR internalization was impaired Shc tyrosine
phosphorylation and MAPK activation In summary, most
of the acute actions of insulin could be initiated by activation
of the plasma membrane-localized insulin receptor
While the activation of the insulin signaling cascade
appears to be independent of IR internalization, tyrosine
phosphatase activity towards IR is largely observed in
endosomes (reviewed in [111,113]) Studies in rat hepatoma
cells demonstrated that internalized IRs were
dephosphory-lated and inactivated prior to recycling back to the plasma
membrane [114] Using isolated rat liver endosomes, Faure
et al showed that a substantial amount of IR PTP activities
is tightly associated with the endosomes This activity resists
the 0.6MKCl treatment of the endosomal membrane, but
Triton X-100 totally abolishes dephosphorylation [115,116]
These studies strongly suggest that the endosome is a major site of IR dephosphorylation However, due to the large number of phosphotyrosine residues on the IR, and the complexity of insulin signaling, the plasma membrane localized IR should not be discarded as an important site of PTP action
For rPTPs such as LAR and rPTPa, the plasma membrane is the obvious location for IR dephosphorylation
As previously discussed, membrane targeting of these rPTPs seems to be necessary for IR dephosphorylation Yet, LAR has also been detected in rat hepatic endosomes [34] Although the kinetics of LAR internalization upon insulin administration was much slower ( 30 min), compared to that of IR ( 2–5 min), incubation of endosomal fractions with antibodies against LAR reduced IR dephosphorylation
by about 28% In addition, subcellular fractionation of rat adipocytes showed that both LAR and rPTPa are present in heavy microsomes [117] Although the identity of these heavy microsomes was not determined, the presence of increased
IR in the same fraction after insulin stimulation suggests that these membranes likely contain endosomal compartments Amongst the intracellular PTPs, PTP-1B is a clear physiological regulator of the IR, and perhaps IRS proteins
as well Although a truncated form of PTP-1B was initially identified in the cytosolic fraction of human placenta, the subcellular characterization of full length PTP-1B demon-strated its predominant localization in the ER through an association with its C-terminal 35 amino acids [81,82] Other
Fig 3 Model of coordinated PTP action on the insulin signaling pathway Different PTPs may act on the IR in various compartments within the cell For example, the transmembrane phosphatases LAR and rPTP-a may predominantly act at the plasma membrane on either the receptor or downstream substrates On the other hand, PTP-1B could act on IR and IRS-1 at the plasma membrane and/or endosomes Finally, the cytosolic PTP, SHP-2, could potentially be recruited to many sites of insulin action However, the role of SHP-2 is mainly to transmit positive signals from the
IR How these PTPs coordinate their action on the insulin signaling pathway remains to be determined.
Trang 7reports indicated that substantial amounts of full length
PTP-1B are also found in the cytosol of rat fibroblasts and
skeletal muscle [28] In rat adipocytes, PTP-1B was found in
the light microsome fraction and to a lesser extent, the
cytosol and heavy microsomes [117] However,
immuno-blotting failed to reveal the presence of PTP-1B in rat liver
endosomes [116] Thus PTP-1B could dephosphorylate the
IR in the light and heavy microsomes, or cytosolic PTP-1B
may be recruited to the appropriate site The precise
localization where PTP-1B dephosphorylates the IR and the
mechanism of PTP-1B translocation to the site of IR
dephosphorylation remain to be elucidated
Finally, in response to insulin, significant amounts of
IRS-1 and IRS-2 are also associated with internal
mem-branes in rat adipocytes [117–119] Furthermore, insulin
stimulation in rat liver increases the association of active
IRS-1, IRS-2, and PI3-kinase to endosomal fractions [120]
These data further show that there is a complex spatial
control in insulin receptor signaling of the various molecules
that are involved and support an important role of the
subcellular localization of both the tyrosine kinases, their
substrates and the PTPs involved in insulin signaling
C O N C L U S I O N S A N D P R O S P E C T S
In contrast to what we have depicted in Fig 1, the
metabolic and mitogenic pathways emanating from the IR
are diverse and complex [121] Although not limited to this,
the action of PTPs represents an important aspect in both
the transmission and attenuation of insulin signaling
Indeed, many studies have been aimed at developing
inhibitors towards these PTPs that might circumvent insulin
resistance and treat type II diabetes Currently, both
PTP-1B and LAR are strong candidates for inhibitor design
studies, although PTP-1B has been the major focus due to
its smaller size, the remarkable data from the knockout
mice, and the availability of structural and kinetic data
An emerging theme that requires further study is how the
coordinate actions of several PTPs may regulate insulin
signaling (Fig 3) As a cytosolic protein, SHP-2 could
potentially be recruited to many sites of insulin action and
positively participate in signal transduction, either through
direct binding with the IR, or through adapter molecules
such as IRS proteins On the other hand, the rPTPs probably
dephosphorylate the IR (or IRS proteins) at the plasma
membrane, although evidence suggests other subcellular
compartments are a possibility as well For PTP-1B, several
sites of insulin action seem possible It will be interesting to
determine how different PTPs might temporally, as well as
spatially, regulate insulin signaling under normal
physiolo-gical conditions and in pathophysiolophysiolo-gical states such as
diabetes Finally, it still remains to be determined whether
different PTPs may act on specific phosphotyrosine residues
on the IR, thus providing another level of specificity
A C K N O W L E D G E M E N T S
We wish to thank John Wagner for critical reading of the manuscript
and helpful discussions A C is a recipient of a Medical Research
Council studentship N D is a recipient of a Canadian Institutes of
Health Research doctoral award F G is a recipient of a Human
Frontiers postdoctoral fellowship M L T is a Canadian Institutes of
Health Research Scientist.
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