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ARTICLE |
Vß3 Integrin Regulates Insulin-Like Growth Factor I (IGF-I) Receptor Phosphorylation by Altering the Rate of Recruitment of the Src-Homology 2-Containing Phosphotyrosine Phosphatase-2 to the Activated IGF-I Receptor
University of North Carolina Department of Medicine, Division of Endocrinology and Metabolism, Chapel Hill, North Carolina 27599-7170
Address all correspondence and requests for reprints to: David R. Clemmons, M.D, CB 7170, 6111 Thurston-Bowles, Division of Endocrinology, University of North Carolina, Chapel Hill, North Carolina 27599-7170. E-mail: endo{at}med.unc.edu.
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Abstract |
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Vß3 integrin is an important determinant of IGF-I-stimulated receptor phosphorylation and biological actions. Blocking ligand occupancy of Vß3 with the distintegrin echistatin reduces IGF-I-stimulated receptor phosphorylation, and it inhibits cellular migration and DNA synthesis responses to IGF-I. We have shown that recruitment of the tyrosine phosphatase Src-homology 2-containing phosphotyrosine phosphatase-2 (SHP-2) to the IGF-I receptor (IGF-IR) is an important determinant of the duration of IGF-IR phosphorylation. These studies were undertaken to determine whether an alteration in the recruitment of SHP-2 to the receptor in the presence of echistatin could account for the decrease in receptor phosphorylation. Following an overnight exposure of smooth muscle cell cultures to echistatin, the addition of IGF-I was accompanied by rapid dephosphorylation of IGF-IR compared with cells exposed to media alone. This was associated with an increase in the rate of SHP-2 recruitment to the IGF-IR. In cells expressing a catalytically inactive form of SHP-2, prior exposure to echistatin had no effect on the rate of receptor dephosphorylation. In contrast to the usual physiologic situation in which following IGF-I exposure SHP-2 is recruited to IGF-IR via SHP-2 substrate-1 (SHPS-1) in the presence of echistatin, SHPS-1 was not used for SHP-2 recruitment. Our findings show that IRS-1 may substitute for SHPS-1 under these conditions. These results demonstrate that the activation state of Vß3 is an important regulator of the duration of IGF-IR phosphorylation and subsequent downstream signaling and that this regulation is mediated through changes in the subcellular localization of SHP-2. |
Introduction |
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Vß3 integrin receptor is required for normal IGF-I receptor (IGF-IR) function in response to IGF-I because blocking Vß3 ligand occupancy using the disintegrin echistatin inhibits IGF-IR and IRS-1 phosphorylation and blocks IGF-I-stimulated cell migration, proliferation, and protein synthesis (6, 7). Because the phosphorylation status of proteins is maintained by a balance between the activity of tyrosine kinases and tyrosine phosphatases, it was probable that echistatin was exerting its effect on IGF-IR phosphorylation by modulating one or both of these events.
We have recently reported that the duration of IGF-IR phosphorylation in smooth muscle cells is regulated by the association of the tyrosine phosphatase Src-homology 2-containing phosphotyrosine phosphatase-2 (SHP-2) with the phosphorylated IGF-IR (8). IGF-IR phosphorylation leads to the rapid phosphorylation of tyrosines contained in the cytoplasmic domain of the membrane associated protein SHPS-1. This generates high affinity binding sites for the tyrosine phosphatase SHP-2, which is then recruited from the cytosol to SHPS-1. Subsequently, SHP-2 is recruited to the IGF-IR following its activation, and this results in dephosphorylation of the receptor that attenuates signaling from the receptor and provides a regulatory mechanism to attenuate downstream signaling.
Because both the phosphorylation of SHPS-1 and the recruitment of SHP-2 from the cytosol have been shown to be regulated by integrin receptor engagement (9, 10, 11, 12), we hypothesized that the association of echistatin with the Vß3 integrin receptor could be altering IGF-IR phosphorylation by altering SHP-2 recruitment to IGF-IR.
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Materials and Methods |
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Porcine aortic smooth muscle cells (pSMCs) were isolated as previously described (13) and maintained in DMEM supplemented with glucose (4.5 g/liter), penicillin (100 U/ml), streptomycin (100 µg/ml), and 10% FBS in 10-cm tissue culture plates. The cells were used between passages 5 and 16.
Transfection of pSMCs
The pSMCs (passage 4–5) were transfected with an inactive SHP-2 that was generated by using the PCR to replace cysteine (469) with a serine in the catalytic site of SHP-2 followed by ligation into the pMEP4 expression vector as described previously (8). This single substitution generates a dominant negative SHP-2 mutant. Cells were also transfected with the empty vector alone. Hygromycin-resistant pSMCs were selected maintained in DMEM-high containing 15% FBS and 100 µg/ml hygromycin and screened as described previously (8, 14). Transfected pSMCs were used in subsequent experiments between passages 6 and 20.
Cell lysis
Cells were incubated overnight in serum-free medium (SFM) and then exposed to 100 ng/ml IGF-I for the appropriate length of time before lysis in ice-cold lysis buffer: 50 mM Tris-HCl (pH 7.5), 150 mM NaCl, 1% Nonidet P-40, 0.25% sodium deoxycholate, 1 mM EGTA plus 1 mM sodium orthovanadate, 1 mM sodium fluoride, 1 mM phenylmethylsulfonyl fluoride, 1 µg/ml pepstatin A, 1 µg/ml leupeptin, and 1 µg/ml aprotinin. The lysates were clarified by centrifugation at 14,000 x g for 10 min. Immunoprecipitation was then carried out as described below.
To test the effect of the various inhibitors on SHP-2 association with the IGF-IR following overnight incubation in SFM, the cells were incubated with either 0.1% dimethylsulfoxide (vehicle) or the appropriate inhibitor (1 µM Ly294002 or 50 µM PD98059) for 30 min before the addition of IGF-I.
Immunoprecipitation
The supernatants were incubated overnight at 4 C with the appropriate antibody (IGF-IR, SHP-2, or SHPS-1 using a 1:500 dilution). Immune complexes were then precipitated by adding protein A-Sepharose and incubating for a further 2 h at 4 C. The samples were then centrifuged at 14,000 x g for 10 min, and the pellets washed four times with lysis buffer. The pellet was resuspended in 45 µl of reducing Laemmeli buffer, boiled for 5 min, and the proteins separated by SDS-PAGE, 8% gel.
Western immunoblotting
Following SDS-PAGE, the proteins were transferred to a polyvinyl difluoride membrane. The membranes were blocked in 1% BSA in Tris-buffered saline with 0.1% Tween for 2 h at room temperature. The membranes were incubated with one of four primary antibodies (IGF-IR, SHP-2, SHPS-1, or PY99 all at a dilution of 1:500) overnight at 4 C and then washed three times in Tris-buffered saline with 0.1% Tween. Binding of the peroxidase-labeled antibody was visualized using enhanced chemiluminescence following the manufacturer’s instructions (Pierce Chemical Co., Rockford, IL) and either exposure to autoradiographic film or detection using the GeneGnome charge-coupled device imaging system (Syngene UK Ltd., Cambridge, UK).
Band intensities were measured by scanning densitometry and analyzed using NIH Image, version 1.61. The Student’s t test was used to compare differences between treatments. The results that are shown for each experiment are representative of at least three separate experiments with similar results.
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Results |
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). This experiment was repeated three times with similar results, and the results of the three experiments are shown in Fig. 2.
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Figure 1
shows that, in the presence of echistatin, there is an increase in the basal association of SHP-2 with the IGF-IR before IGF-I exposure and a marked increase in its association with the IGF-IR following a 5-min exposure to IGF-I. In contrast, in cells that were not incubated with echistatin SHP-2 association was not seen until 20 min after IGF-I exposure. This result suggests that the enhanced association of SHP-2 with the IGF-IR after 5 min could account for the described receptor phosphorylation decrease at 10 and 20 min and that this change is due to an increased rate of receptor dephosphorylation.
IGF-I-stimulated SHP-2 recruitment to the IGF-IR in the presence of echistatin is mediated via a phosphatidylinositol 3-kinase (PI3K)-dependent pathway.
Because it is known that activation of the IGF-IR can activate both the PI3K and MAPK pathways, we tested the effect of specific inhibitors of these two pathways on the IGF-I-stimulated recruitment of SHP-2 to the IGF-IR in the presence of echistatin. Figure 3 shows that the recruitment of SHP-2 to the IGF-IR that occurs in response to echistatin treatment is inhibited in the presence of the specific PI3K inhibitor Ly294002. In contrast, it is not inhibited by the MAPK inhibitor PD 98059. This suggests that the recruitment of SHP-2 to the IGF-IR in the presence of echistatin is mediated via a PI3K-dependent pathway.
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shows that, in the absence of echistatin, IGF-I stimulates SHP-2 recruitment to SHPS-1, confirming our previous report. However, in the presence of echistatin there is no recruitment of SHP-2 to SHPS-1.
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shows that, whereas IGF-I can stimulate a rapid increase in SHPS-1 phosphorylation, this increase is blocked in the presence of echistatin. Therefore, in the presence of echistatin, SHP-2 is not recruited to the IGF-IR via this mechanism. However, because there is an increase in the amount of SHP-2 recruited to the receptor at 0, 5, and 10 min, this suggests that echistatin binding to Vß3 or its inhibition of binding of Vß3 ligands such as vitronectin or fibronectin activates an alternative mechanism to recruit SHP-2 to the IGF-IR.
SHP-2 is recruited to IRS-1 in the presence of echistatin
Because SHP-2 is not recruited to the IGF-IR via SHPS-1 in the presence of echistatin, we next considered other candidates for the recruitment of SHP-2. We tested whether the effect of echistatin was mediated via the recruitment of SHP-2 to several proteins (Gab-1, Gab-2, and IRS-1) that are known to bind to both the IGF-IR and SHP-2. Figure 5 shows that following IGF-I stimulation SHP-2 is recruited to IRS-1 after a 20-min treatment with IGF-I, and when cells are pretreated with echistatin there is a significant increase in SHP-2 recruitment to IRS-1 following a 5-min exposure to IGF-I. Because the time at which SHP-2 is associated with IRS-1 in both the presence or absence of echistatin corresponds to the time at which SHP-2 is binding to the IGF-IR, this suggests that IRS-1 may be involved in the alternative recruitment pathway. In contrast, the recruitment of SHP-2 to both Gab-1 and Gab-2 was not affected by echistatin (data not shown).
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, it can be seen that in cells expressing the mutated form of SHP-2 exposure to echistatin does not result in a decrease in IGF-IR phosphorylation as was seen in cells expressing wild-type SHP-2. This change is not due to the absence of SHP-2 recruitment because cells expressing the mutated form of SHP-2 that were preincubated with echistatin still show association of SHP-2 with the receptor at 0, 5, and 10 min. This contrasts with the cells expressing only endogenous SHP-2 in which IGF-IR phosphorylation is significantly reduced in the presence of echistatin after 10 min, and this change in its phosphorylation state is associated with an increase in SHP-2 association with the receptor at 5 min. The increase in basal IGF-IR association between catalytically inactive form of SHP-2 (SHP-2 C-S) and wild-type SHP-2 is presumably due to the lack of phosphatase activity and hence tighter association with the receptor and lack of disassociation. The lack of SHP-2 association with the IGF-IR in the absence of echistatin in cells expressing the SHP-2 C-S mutant is consistent with our previous report in which we demonstrated that catalytically inactive SHP-2 is not recruited to the IGF-IR as it is retained on SHPS-1 (8). Thus, the absence of an echistatin effect on receptor phosphorylation in the cells expressing the catalytically inactive SHP-2 strongly suggests that the early recruitment of SHP-2 to the receptor that is induced by echistatin and the subsequent increase in its recruitment to the receptor at 5 min after IGF-I treatment is responsible for the acceleration in the rate of receptor dephosphorylation.
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Discussion |
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Vß3 resulted in a change in the intensity or duration of IGF-IR phosphorylation and therefore downstream signaling, we initially compared the IGF-IR phosphorylation time course in response to IGF-I in the presence or absence of echistatin. Because the level of phosphorylation at the early time points was similar, this suggested that exposure of the cells to echistatin had no inhibitory effect on the induction of tyrosine kinase activity of the receptor. However, because the rate of the decrease in the intensity of the phosphorylated IGF-IR band was more rapid in the presence of echistatin, the data suggested that blocking ligand occupancy of the Vß3 integrin receptor resulted in an increase in the rate at which the receptor was dephosphorylated. We have shown recently that, under normal conditions, the duration of IGF-IR phosphorylation following ligand binding is regulated by the recruitment of the tyrosine phosphatase SHP-2 (8). From our studies presented here, we propose that the accelerated rate of dephosphorylation that occurs in response to IGF-I following exposure to echistatin results from an alteration in the recruitment of SHP-2. This is supported by our initial time course studies in which we demonstrated that SHP-2 was recruited to the receptor by exposure to echistatin alone, and there was a much greater increase in SHP-2 at early time points after IGF-I exposure in the presence of echistatin. This conclusion is supported by our observation that cells that expressed a catalytically inactive form of SHP-2 showed recruitment of SHP-2 to the receptor following echistatin exposure but no increase in receptor dephosphorylation.
These data suggest that the activation state of the Vß3 integrin receptor is an important modulator of IGF-I signaling and that it functions by regulating the subcellular localization of SHP-2. This is consistent with a previous report in which it was shown that growing mouse embryo fibroblasts on fibronectin before exposure to platelet-derived growth factor increased the association of SHP-2 with the platelet-derived growth factor-ß receptor (12).
These findings raise the question of how echistatin binding to Vß3 causes a change in the rate of SHP-2 recruitment to the IGF-IR. We have shown that, under normal conditions, SHP-2 is recruited to the IGF-IR via SHPS-1. SHPS-1 is a transmembrane glycoprotein with four potential tyrosine phosphorylation sites and SH2 binding motifs in its cytoplasmic domain (9, 10, 14, 15). It is phosphorylated on these tyrosines, thereby recruiting and activating SHP-2 in response to ligand occupancy of various growth factor receptors including the insulin receptor (9, 10, 14, 15). We have demonstrated that this is the mechanism by which SHP-2 is recruited to the IGF-IR (8). However, in the presence of echistatin SHPS-1 is not phosphorylated in response to IGF-I, and there is no SHP-2 recruited to the IGF-IR via SHPS-1. These data suggest that in the presence of echistatin an alternative mechanism is used to recruit SHP-2 from the cytosol to the receptor, and this occurs at earlier time points compared with the normal SHPS-1 recruitment cycle. An alternative mechanism for SHP-2 recruitment to the membrane has been demonstrated in a recent study that showed that Gab1 functions to target-activated SHP-2 to the membrane in response to EGF stimulation (16). Other proteins that have been shown to bind to activated SHP-2 include Gab2 (17), IRS-1 (18), and platelet/endothelial cell adhesion molecule (19). Because IRS-1 binds to the IGF-IR, our data demonstrating that the recruitment of SHP-2 to IRS-1 in response to IGF-I is also accelerated in the presence of echistatin suggest that IRS-I may play a role the recruitment of SHP-2 to the IGF-IR. However, unlike the normal mechanism, echistatin induction of SHP-2 recruitment also occurs in the absence of ligand occupancy of the IGF-IR. Because there is no detectable association between IRS-1 and SHP-2 in the absence of IGF-I stimulation, IRS-1 is presumably not responsible for this initial basal association detectable in the presence of echistatin.
In addition to the premature recruitment of SHP-2 to the IGF-IR, it is also possible that echistatin is resulting in the premature activation of SHP-2. SHP-2 can be activated by both its association with phosphorylated tyrosines and also by its own phosphorylation. Therefore, it is possible that echistatin may be activating a tyrosine kinase that results in the phosphorylation of SHP-2 contributing to the premature dephosphorylation of the IGF-IR.
It is somewhat surprising that SHPS-1 was not phosphorylated in response to IGF-I in the presence of echistatin because maximal phosphorylation of SHPS-1 occurs rapidly, at a point when IGF-IR phosphorylation is equivalent in the presence or absence of echistatin. This raises the possibility that echistatin binding to Vß3 has a direct effect on SHPS-1 phosphorylation independent of its effects on IGF-IR phosphorylation. SHPS-1 phosphorylation has been shown to be stimulated by integrin occupancy during cell attachment in a focal adhesion kinase- and c-Src kinase-dependent manner, demonstrating a direct link between integrin activation and SHPS-1 phosphorylation (9). Our data, which use a system in which the cells are stably attached, show that SHPS-1 phosphorylation in response to growth factor stimulation requires appropriate integrin ligand occupancy. Recently, integrin associated protein, an important cofactor for maximal enhancement of the activity of Vß3 integrin ligand binding and Vß3-mediated signaling, has been shown to bind SHPS-1 (20). The relationship between integrin associated protein binding to SHPS-1 and the regulation of SHPS-1 phosphorylation is unknown, but it is interesting to speculate that the activation state of the Vß3 may be an important variable that alters the consequences of this interaction and thereby modulates the susceptibility of SHPS-1 to phosphorylation.
We have previously shown that echistatin inhibits IGF-I-stimulated cell migration, protein, and DNA synthesis (6, 7), yet we have shown here that following a 5-min exposure to IGF-I, IGF-IR phosphorylation levels are equivalent in the presence or absence of echistatin. This suggests that either it is the duration of IGF-IR phosphorylation that is crucial for determining the intensity of the cellular response to IGF-I. Myers et al. (18) have shown in 32D cells that mutation of IRS-1 such that it will not bind SHP-2 leads to more intense IRS-1 phosphorylation, PI3K activation, and protein synthesis in response to insulin stimulation. Thus, SHP-2 was interpreted to be a negative regulator of downstream signaling. Our studies further suggest that this negative regulation can occur at the level of the IGF-IR leading to abrogation of multiple biological actions.
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Acknowledgments |
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Footnotes |
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Abbreviations: FBS, Fetal bovine serum; IGF-IR, IGF-I receptor; IRS-1, insulin receptor substrate-I; PI3K, phosphatidylinositol 3-kinase; pSMC, porcine smooth muscle cells; SFM, serum-free medium; SHC, Srchomology collagen; SHP-2, Src-homology 2-containing phosphotyrosine phosphatase-2; SHP-2 C-S, catalytically inactive form of SHP-2; SHPS-1, SHP-2 substrate.
Received April 11, 2002.
Accepted for publication July 8, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IR-3). J Biol Chem 268:2655–2661V-ß3 integrin is necessary for smooth muscle cells to migrate in response to insulin-like growth factor. Proc Natl Acad Sci USA 93:2482–2487Vß3 integrin inhibits insulin-like growth factor I signaling in vascular smooth muscle cells. Proc Natl Acad Sci USA 95:11217–11222This article has been cited by other articles:
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 |
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