PRL-3 promotes the motility, invasion, and metastasis of LoVo colon cancer cells through PRL-3-integrin β1-ERK1/2 and-MMP2 signaling
- Lirong Peng†1,
- Xiaofang Xing†1,
- Weijun Li†1,
- Like Qu1,
- Lin Meng1,
- Shenyi Lian1,
- Beihai Jiang1,
- Jian Wu1 and
- Chengchao Shou1Email author
© Peng et al; licensee BioMed Central Ltd. 2009
Received: 1 July 2009
Accepted: 24 November 2009
Published: 24 November 2009
Phosphatase of regenerating liver-3 (PRL-3) plays a causative role in tumor metastasis, but the underlying mechanisms are not well understood. In our previous study, we observed that PRL-3 could decrease tyrosine phosphorylation of integrin β1 and enhance activation of ERK1/2 in HEK293 cells. Herein we aim to explore the association of PRL-3 with integrin β1 signaling and its functional implications in motility, invasion, and metastasis of colon cancer cell LoVo.
Transwell chamber assay and nude mouse model were used to study motility and invasion, and metastsis of LoVo colon cancer cells, respectively. Knockdown of integrin β1 by siRNA or lentivirus were detected with Western blot and RT-PCR. The effect of PRL-3 on integrin β1, ERK1/2, and MMPs that mediate motility, invasion, and metastasis were measured by Western blot, immunofluorencence, co-immunoprecipitation and zymographic assays.
We demonstrated that PRL-3 associated with integrin β1 and its expression was positively correlated with ERK1/2 phosphorylation in colon cancer tissues. Depletion of integrin β1 with siRNA, not only abrogated the activation of ERK1/2 stimulated by PRL-3, but also abolished PRL-3-induced motility and invasion of LoVo cells in vitro. Similarly, inhibition of ERK1/2 phosphorylation with U0126 or MMP activity with GM6001 also impaired PRL-3-induced invasion. In addition, PRL-3 promoted gelatinolytic activity of MMP2, and this stimulation correlated with decreased TIMP2 expression. Moreover, PRL-3-stimulated lung metastasis of LoVo cells in a nude mouse model was inhibited when integrin β1 expression was interfered with shRNA.
Our results suggest that PRL-3's roles in motility, invasion, and metastasis in colon cancer are critically controlled by the integrin β1-ERK1/2-MMP2 signaling.
Colorectal cancer ranks third in the incidence of cancer in the world, and metastasis is the main death cause. Although causes and genetic bases of tumorigenesis vary greatly, key events required for metastasis are similar, including alteration of adhesion ability, enhancement of motility, and secretion of proteolytic enzymes to degrade extracellular matrix (ECM) and vascular basement membrane; all these steps are orchestrated by a plethora of signaling events. Phosphatase of regenerating liver-3 (PRL-3), also known as PTP4A3, encodes a 22-kilodalton protein tyrosine phosphatase and is characteristic of a CAAX motif for prenylation at the carboxyl terminus . At mRNA level, it is detected primarily in skeletal and cardiac muscles, somewhat in pancreas, but rarely in brain, lungs, liver, kidneys, and placenta . However, it is highly expressed in multiple cancer cell lines and vascular endothelial cells [3–5]. Initially, PRL-3 was found to be up-regulated in liver metastases of colorectal cancer, but was low or absent in normal colorectal epithelium, adenoma, and primary lesions . Later, we and other several groups provided strong evidence to show that PRL-3 is overexpressed in diverse malignancies, including colorectal, breast, gastric, and ovarian cancers, and its expression is correlated with disease progression and survival [7–14]. A recent study by Molleví et al. demonstrated that tumor microenvironment play a critical role in regulating PRL-3 expression. To date, PRL-3 is not only thought as a potential prognostic factor for diagnosis and survival of multiple type cancers, but also has a therapeutic implication, because its expression at the invasive margin of tumor predicted resistance to radiotherapy and unfavorable survival for patients [16, 17].
Previous studies also revealed that PRL-3 plays a causative role in promoting cell motility, invasion, and metastasis [18, 19]. However, little is known about the molecular mechanisms by which PRL-3 promotes motility, invasion and metastasis. It was reported that PRL-3 exerted its functions by regulating Rho family GTPase , activating Src , and modulating PI3K-Akt pathway  in a context-dependent manner. In addition, a transcriptional regulation of PRL-3 by p53 has been reported . In our previous study, we found a physical association between PRL-3 and integrin α1 by yeast two-hybrid and GST-pull down assays . We also observed decreased tyrosine phosphorylation of integrin β1 and enhanced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in exogenous PRL-3-stably expressing HEK293 cells. Integrins is a large family of heterodimeric cell-surface receptors and integrin-mediated extracellular signals stimulate a variety of intracellular signaling events, including tyrosine phosphorylation and mitogen-activated protein kinase (MAPK) cascades, leading to the ERK activation, which is involved in cell survival and proliferation, and promotes metaplasia and tumor development [25–28]. Therefore, in the present study, we investigated the functional roles of integrin signaling and ERK1/2 activation in PRL-3-promoted motility, invasion, and metastasis in colon cancer cell LoVo. We verified the enhancement of ERK1/2 phosphorylation in PRL-3-stably expressing LoVo (LoVo-P) cells. Knockdown of integrin β1 not only inhibited PRL-3-induced ERK1/2 phosphorylation, but also abrogated PRL-3-mediated motility, invasion, and lung metastasis in nude mice. In the downstream of integrin β1 pathway, ERK1/2 phosphorylation and MMP2 activity were found to be responsible for PRL-3-mediated cell invasion. Collectively, our study demonstrated that the integrin β1-ERK1/2 and -MMP2 signaling plays critical roles in PRL-3-promoted motility, invasion, and metastasis of colon cancer cells.
Reagents and cell culture
We purchased anti-integrin β1 anitbody (MAB 1965) from Chemicon (Temecula, CA). Anti-phosphorylated tyrosine antibody 4G10 was from Millipore (Billerica, MA). Monoclonal antibody 3B6 against PRL-3 was generated as previously described . Polyclonal antibody to PRL-3 was from Sigma. Antibodies against ERK1/2 and phosphorylated ERK1/2 (p-ERK1/2) were from Upstate (Beverly, MA). Anti-p53 antibody (DO-1) was from Santa Cruz. U0126 was from Cell Signaling (Beverly, MA). Colon cancer cell line LoVo (ATCC, Manassas, VA) were maintained in Ham's F12K medium (Invitrogen) supplemented with 10% fetal calf serum.
Plasmids and transfection
Myc-tagged human PRL-3 cDNA was inserted into pcDNA3.1 at BamH I/Xba I sites to generate a mammalian expression plasmid pcDNA3.1-PRL-3. Then, pcDNA3.1-PRL-3 and pcDNA3.1 were transfected into LoVo cells with Lipofectamine 2000 (Invitrogen) to generate PRL-3-stably expressing and control cells, respectively. After 4 weeks of selection with 600 μg/mL of Geneticin (Invitrogen), expression of PRL-3 was verified by RT-PCR and Western blot. Plasmid pEGFP-C1-PRL-3 was generated by ligating BamH I/EcoR I digested full-length PRL-3 to Bgl II/EcoR I digested pEGFP-C1 vector (Clontech, Palo Alto, CA).
Integrin β1-specific siRNA, synthesized by Sigma-Aldrich Corporation (St. Louis, MO), was designed to silence all splices of human integrin β1 mRNA. The sequence was: sense, 5'-GGAAAUGGUGUUUGCAAGUdTdT-3'; antisense, 5'-ACUUGCAAACACCAUUUCCdTdT-3'. It was scrambled to generate a negative control. Lentivirus vectors expressing short hair-pin (sh)RNA targeting PRL-3 or integrin β1 were constructed, packed, and purified by GeneChem Corporation (Shanghai, China), and was manipulated according to the Biological Institutional Committee of Beijing.
Western blot and immunoprecipitation
Cells were homogenized in lysis buffer (50 mM Tris-HCl, pH 7.5, 150 mM NaCl, 1% NP-40, 1 mM DTT, 1 mM phenylmethylsulfonyl fluoride, 10 mM NaF, 1 mM Na3VO4, 1 × protease cocktail) for 20 min at 4°C. The supernatant was collected after centrifugation at 12,000 × g for 20 min at 4°C and subjected to Western blot or immunoprecipitation as previously described . Documentation of blots was performed by scanning with an EPSON PERFECTION 2580 scanner and acquired images were adjusted by the Auto-Contrast command of Photoshop CS (Adobe, San Jose, CA).
Consecutive 4-μm paraffin-embedded sections of colon cancer tissues were obtained from the Department of Pathology of the Beijing Cancer Hospital and Institute. Staining of PRL-3 or p-ERK1/2 protein by an immunohistochemical assay was performed as previously described . Specimens with more than 10% positive-staining cancer cells were classified as positive.
Motility and invasion assays
For transwell chamber-based motility and invasion assays, equal amounts of cells were loaded into an insert provided with serum-free medium and allowed to pass through an 8-μm-pore polycarbonate filter, which had been either pre-coated with 100 μg of Matrigel (Becton Dickinson, San Jose, CA) for invasion assay or left uncoated for motility assay. Medium supplemented with 10% fetal calf serum was added to the bottom chamber. Cells on the upper surface of filters were wiped out after 24 h (motility assay) or 48 h (invasion assay), and those on the undersurface were stained with 1% amino toluene blue and counted under a microscope.
In vitro wound healing assay
Cells were seeded onto 6-well plates at a sub-confluent density. After 12 h, a line was scrapped out on the cell monolayer by a 200-μl pipet tip and the width of this wound line was photographed using an inverted microscope (ECLIPSE TS100, Nikon, Japan) at a 24 h interval. The motility speed of cells was assessed by the healing degree of the wound line. The experiment was repeated three times independently.
To visualize green fluorescent protein (GFP) tagged PRL-3, LoVo cells were transfected with pEGFP-C1-PRL-3 and seeded onto coverslips. For indirect immunofluorescence assays, pEGFP-C1-PRL-3 transiently transfected LoVo cells were fixed with 4% paraformaldehyde for 10 min at room temperature, permeabilized with 0.5% Triton X-100/phosphate-buffered saline for 5 min, and blocked with 3% bovine serum albumin for 30 min. Anti-integrin β1 antibody was then added to the cells, followed with a tetramethyl rhodamine isothiocyanate-conjugated secondary antibody. After washing with phosphate-buffered saline/Tween-20, coverslips were mounted on glass slides with 50% glycerol/phosphate-buffered saline and imaged using a Leica SP2 confocal system (Leica Microsystems, Dresden, Germany).
We performed animal experiments in accordance with the Experimental Animal Management Ordinance approved by the Scientific and Technological Committee of China. Every of the five experimental groups had eight 4 to 6-week-old female nude BALB/c mice (Lian-Tong-Li-Hua Corporation, Beijing, China). Each mouse was injected via tail vein with 2.5 × 106 LoVo control (LoVo-C) or LoVo-PRL-3 (LoVo-P) cells; the latter were pre-infected with lentivirus interfering with PRL-3, integrin β1, or mock control, respectively. Two months later, all animals were sacrificed, and 4-μM paraffin-embedded sections of lung and liver tissues were prepared. The sections were stained with hematoxylin and eosin and examined for the presence of metastatic tumor foci under a microscope.
The zymographic analysis was adapted from Surgucheva IG et al. . Cells were grown to 70-80% confluence on 10-cm plates, washed twice with PBS, and cultured in serum-free medium for another 36 h. Next, medium was concentrated to one-tenth volume and measured for protein concentration. Appropriate volume of medium with equivalent amount of protein was subjected to electrophoresis in 10% gel containing 0.1% gelatin. After electrophoresis, the gelatin gel was washed twice with 2.5% Triton X-100 and allowed to perform an enzyme reaction in Tris buffer (50 mM Tris-HCl at pH 7.4, 200 mM NaCl, and 10 mM CaCl2) overnight at 37°C. Next, it was stained with 0.5% Coomassie Brilliant Blue R-250 and de-stained with 5% acetic acid containing 10% methanol.
Statistical analysis software package SPSS 12.0 (SPSS Inc., Chicago, IL) was used to perform Poisson distribution events test and Chi-square test. P value less than 0.05 was considered statistically significant.
PRL-3 is associated with integrin β1
To better support this result, we examined subcellular localization of transiently overexpressed GFP-tagged PRL-3 and endogenous integrin β1 in LoVo cells by an indirect immunofluorescence assay. Figure 1B showed that both GFP-tagged PRL-3 and fluorescent antibody-labeled integrin β1 were expressed in cytoplasmic membrane. Dual-color merged confocal imaging demonstrated that PRL-3 was colocalized with integrin β1 (Figure 1B).
Previously, we noticed a decrease of integrin β1 tyrosine phosphorylation in PRL-3-stably expressing HEK293 cells . Therefore, we checked the effect of PRL-3 on tyrosine phosphorylation of integrin β1 in LoVo cells. Using equal amount of lysates from LoVo-C and LoVo-P cells, we immunoprecipiated tyrosine-phosphorlyated integrin β1 with a phospho-tyrosine specific antibody, respectively, and immunoblotted it with anti-integrin β1 antibody. Tyrosine-phosphorylated integrin β1 was found in both cells, however, it was decreased in LoVo-P cells (Figure 1C), though integrin β1 protein expressed at similar level. This result substantiated PRL-3's role in regulating tyrosine phosphorylation of integrin β1.
Integrin β1 is necessary for PRL-3-induced cell motility and invasion in vitro
Integrin β1 is required for PRL-3-induced metastasis in vivo
Metastasis of LoVo-C and LoVo-P Cells in Nude Mice BALB/c
Total number of mice
Number of mice with metastasis
Number of metastatic foci
LoVo-P lentivirus-integrin β1
Integrin β1 is required for PRL-3-induced ERK1/2 activation
PRL-3 promotes cell invasion by altering the balance between MMP2 and TIMP2
To dissect the mechanism of MMPs in PRL-3-promoted cell invasion, gelatinolytic activities of MMP2 and MMP9, two key members of MMP family, were examined by a zymographic assay. In brief, concentrated and normalized serum-free medium of LoVo-C and LoVo-P cells, which contained MMPs secreted by cells, were subjected to electrophoresis in a 10% gel containing the substrate of gelatin and carried out enzymatic reaction. Bright bands contrasting to dark background indicated the absence of gelatin, which had been hydrolyzed by MMPs running to the corresponding molecular weight. Figure 6B showed that MMP2 activity was strongly increased in the culture medium of LoVo-P cells compared to that of LoVo-C cells. No activity of MMP9 was detected in these cells. It is known that activity of MMP2 is regulated by a dynamic balance between MMP2 and its endogenous tissue inhibitor TIMP2 post-translationally [42, 43]. To clarify whether increased MMP2 activity resulted from up-regulation of MMP2 or down-regulation of TIMP2, we examined expression of MMP2 and TIMP2 at both mRNA and protein levels in LoVo-C and LoVo-P cells. MMP2 mRNA was increased in LoVo-P cells, contrary to the decrease of TIMP2 mRNA in LoVo-P cells (Figure 6C, left). At protein level, MMP2 was decreased and TIMP2 were hardly detected in LoVo-P cells (Figure 6C, right). We reasoned that the decrease of MMP2 protein level of LoVo-P cell lysates might result from enhanced secretion of activated MMP2 into the outside of cells or increase of activation-induced MMP2 proteolysis. Therefore, PRL-3 might alter the balance between MMP2 and TIMP2 to facilitate MMP2 activation at multiple levels.
Protein kinases and phosphatases regulate multiple physiological processes [44, 45]. Phosphatases usually function as tumor suppressors, but some of them have stimulatory effects on cancer-associated processes. PRL-3 is a metastasis-promoting phosphatase [47, 48]. It has been found to promote metastasis of a variety of cells, including Chinese hamster ovary cell CHO, mouse melanoma cell B16, and gastric cancer cell SGC7901 [18, 19, 49].
In this study, we examined the roles of integrin β1-ERK1/2 signaling in PRL-3-facilitating metastasis using human colon cancer cell LoVo, colon cancer tissues from patients, and a metastatic mouse model. We found endogenous integrin β1 was associated and colocalized with exogenous PRL-3 in LoVo cells. We tried to explore whether there is a direct interaction between these two molecules by an in vitro binding assay with purified recombinant PRL-3 and cytoplasmic domain of integrin β1, however, no interaction was found (data not shown). It's possible that integrin α1 mediated PRL-3-integrin β1 interaction, because we previously showed that PRL-3 physically interacted with integrin α1 in HEK293 cells . Unfortunately, integrin α1 protein was not detected in LoVo cells. Whereas in both LoVo-P cells and gastric cancer cells BGC823 stably expressing PRL-3 (BGC823-P), which have detectable integrin α1 on the cell membrane, we observed PRL-3-integrin β1 interaction (data not shown), suggesting that such interaction might be indirect and integrin α1-independent, at least for these two cell lines. Besides α1, integrin α2-9 and α V are also integrin β1-binding proteins . Their roles in mediating the PRL-3-integrin β1 interaction deserve further exploration.
Here we demonstrated that stable expression of PRL-3 decreased tyrosine phosphorylation of integrin β1. Tyrosine phosphorylation of integrin β1 has been reported to impair its binding ability with talin . Another study showed that tyrosine dephosphorylation of integrin β1 altered its association with actin . Recently, a large-scale survey of tyrosine kinase activity in non-small cell lung cancer cell lines identified Y783 of integrin β1 as a potential phosphorylation site . However, kinases and phosphatase responsible for tyrosine phoshorylation modification of integrin β1 are unknown. Therefore, it remains to be determined whether phosphorylation modification of integrin β1 is critical for its signaling transduction and necessary for functions of PRL-3 or whether integrin β1 is a substrate of PRL-3.
We also revealed a PRL-3-integrin β1-ERK1/2 pathway in controlling motility and invasion of colon cancer cell LoVo. We showed that both activation of ERK1/2 and the presence of integrin β1 were necessary for PRL-3 to promote motility and invasion. Activation of ERK1/2 by PRL-3 is dependent on integrin β1. Moreover, knockdown of integrin β1 efficiently inhibited PRL-3-mediated lung metastasis of LoVo cells in nude mice with a comparable effect to that of silencing of PRL-3. However, the intermediate signaling events between integrin β1 and ERK1/2 are still unclear. Activation of ERK is stimulated by both soluble growth factors and integrin-mediated adhesion signals. Integrins intersecting the ERK/MAPK pathway at multiple level, and the crosstalk between growth factors and integrin signaling, give rise to complicated integrin signaling networks and distinctive ERK activation signals [53–55]. To find the intersection point of PRL-3 in the integrin signaling networks would contribute to clarifying the PRL-3 promoted motility, invasion and metastasis. Interestingly, PRL-3 has been reported to activate Src kinase to initiate signaling events, culminating in pathways of ERK1/2, Stat3, and p130cas . Src is one of downstream factors of integrin β1 signaling as well as a upstream molecule of ERK activation . Therefore, whether PRL-3 activates ERK1/2 through the integrin β1-Src pathway or others, such as the integrin β1-Grb2 pathway, deserves further exploration. Downstream of the PRL-3-integrin β1-ERK1/2 pathway, we found that MMP2 exerted proteolysis function on ECM, a critical event for cancer metastasis. PRL-3 enhanced gelatin hydrolytic activity of MMP2 by increasing MMP2 mRNA and decreasing TIMP2 mRNA and protein. The imbalance of MMP2/TIMP2 expression might account for high MMP2 enzymatic activity imposed by PRL-3 overexpression. In a recent study, PRL-3 expression level was found to be positively correlated with MMP2 activity in high grade of glioma tissues , supporting our findings about MMP2 activation in LoVo cells. The precise mechanism of PRL-3 in regulating MMP2 remains to be further clarified.
Taken together, our results suggest that PRL-3's roles in motility, invasion, and metastasis in colon cancer are critically controlled by the integrin β1-ERK1/2-MMP2 signalings. Deeper dissecting the regulation of the PRL-3-integrin β1-ERK1/2-MMP2 pathway may have a therapeutic implication for prognosis and treatment for colon cancer metastasis.
extracellular signal-regulated kinase
focal adhesion kinase
green fluorescent protein
Growth factor receptor-bound protein 2
mitogen-activated protein kinases
phosphatase of regenerating liver-3
reverse transcription-polymerase chain reaction
short hair-pin RNA
small interfering RNA
- Src kinase:
This study was supported by the National 973 Program (2009CB521805), National Nature Science Foundation of China (30671024 and 30973407) and Natural Science Foundation of Beijing (5072015).
- Zeng Q, Hong W, Tan YH: Mouse PRL-2 and PRL-3, two potentially prenylated protein tyrosine phosphatases homologous to PRL-1. Biochem Biophys Res Commun. 1998, 244: 421-427. 10.1006/bbrc.1998.8291View ArticlePubMedGoogle Scholar
- Matter WF, Estridge T, Zhang C, Belagaje R, Stancato L, Dixon J, Johnson B, Bloem L, Pickard T, Donaghue M: Role of PRL-3, a human muscle-specific tyrosine phosphatase, in angiotensin-II signaling. Biochem Biophys Res Commun. 2001, 283: 1061-1068. 10.1006/bbrc.2001.4881View ArticlePubMedGoogle Scholar
- Fagerli UM, Holt RU, Holien T, Vaatsveen TK, Zhan F, Egeberg KW, Barlogie B, Waage A, Aarset H, Dai HY: Overexpression and involvement in migration by the metastasis-associated phosphatase PRL-3 in human myeloma cells. Blood. 2008, 111: 806-815. 10.1182/blood-2007-07-101139PubMed CentralView ArticlePubMedGoogle Scholar
- Parker BS, Argani P, Cook BP, Liangfeng H, Chartrand SD, Zhang M, Saha S, Bardelli A, Jiang Y, St Martin TB: Alterations in vascular gene expression in invasive breast carcinoma. Cancer Res. 2004, 64: 7857-7866. 10.1158/0008-5472.CAN-04-1976View ArticlePubMedGoogle Scholar
- Rouleau C, Roy A, St Martin T, Dufault MR, Boutin P, Liu D, Zhang M, Puorro-Radzwill K, Rulli L, Reczek D: Protein tyrosine phosphatase PRL-3 in malignant cells and endothelial cells: expression and function. Mol Cancer Ther. 2006, 5: 219-229. 10.1158/1535-7163.MCT-05-0289View ArticlePubMedGoogle Scholar
- Saha S, Bardelli A, Buckhaults P, Velculescu VE, Rago C, St Croix B, Romans KE, Choti MA, Lengauer C, Kinzler KW, Vogelstein B: A phosphatase associated with metastasis of colorectal cancer. Science. 2001, 294: 1343-1346. 10.1126/science.1065817View ArticlePubMedGoogle Scholar
- Peng L, Ning J, Meng L, Shou C: The association of the expression level of protein tyrosine phosphatase PRL-3 protein with liver metastasis and prognosis of patients with colorectal cancer. J Cancer Res Clin Oncol. 2004, 130: 521-526. 10.1007/s00432-004-0563-xView ArticlePubMedGoogle Scholar
- Wang L, Peng L, Dong B, Kong L, Meng L, Yan L, Xie Y, Shou C: Overexpression of phosphatase of regenerating liver-3 in breast cancer: association with a poor clinical outcome. Ann Oncol. 2006, 17: 1517-1522. 10.1093/annonc/mdl159View ArticlePubMedGoogle Scholar
- Xing X, Peng L, Qu L, Ren T, Dong B, Su X, Shou C: Prognostic value of PRL-3 overexpression in early stages of colonic cancer. Histopathology. 2009, 54: 309-318. 10.1111/j.1365-2559.2009.03226.xView ArticlePubMedGoogle Scholar
- Ren T, Jiang B, Xing X, Dong B, Peng L, Meng L, Xu H, Shou C: Prognostic Significance of Phosphatase of Regenerating Liver-3 Expression in Ovarian Cancer. Pathol Oncol Res. 2009Google Scholar
- Radke I, Gotte M, Kersting C, Mattsson B, Kiesel L, Wulfing P: Expression and prognostic impact of the protein tyrosine phosphatases PRL-1, PRL-2, and PRL-3 in breast cancer. Br J Cancer. 2006, 95: 347-354. 10.1038/sj.bjc.6603261PubMed CentralView ArticlePubMedGoogle Scholar
- Miskad UA, Semba S, Kato H, Yokozaki H: Expression of PRL-3 phosphatase in human gastric carcinomas: close correlation with invasion and metastasis. Pathobiology. 2004, 71: 176-184. 10.1159/000078671View ArticlePubMedGoogle Scholar
- Bardelli A, Saha S, Sager JA, Romans KE, Xin B, Markowitz SD, Lengauer C, Velculescu VE, Kinzler KW, Vogelstein B: PRL-3 expression in metastatic cancers. Clin Cancer Res. 2003, 9: 5607-5615.PubMedGoogle Scholar
- Polato F, Codegoni A, Fruscio R, Perego P, Mangioni C, Saha S, Bardelli A, Broggini M: PRL-3 phosphatase is implicated in ovarian cancer growth. Clin Cancer Res. 2005, 11: 6835-6839. 10.1158/1078-0432.CCR-04-2357View ArticlePubMedGoogle Scholar
- Mollevi D, Aytes A, Berdiel M, Padulles L, Martinez-Iniesta M, Sanjuan X, Salazar R, Villanueva A: PRL-3 overexpression in epithelial cells is induced by surrounding stromal fibroblasts. Molecular Cancer. 2009, 8: 46- 10.1186/1476-4598-8-46PubMed CentralView ArticlePubMedGoogle Scholar
- Wallin AR, Svanvik J, Adell G, Sun XF: Expression of PRL proteins at invasive margin of rectal cancers in relation to preoperative radiotherapy. Int J Radiat Oncol Biol Phys. 2006, 65: 452-458.View ArticlePubMedGoogle Scholar
- Bessette DC, Qiu D, Pallen CJ: PRL PTPs: mediators and markers of cancer progression. Cancer Metastasis Rev. 2008, 27: 231-252. 10.1007/s10555-008-9121-3View ArticlePubMedGoogle Scholar
- Zeng Q, Dong JM, Guo K, Li J, Tan HX, Koh V, Pallen CJ, Manser E, Hong W: PRL-3 and PRL-1 promote cell migration, invasion, and metastasis. Cancer Res. 2003, 63: 2716-2722.PubMedGoogle Scholar
- Wu X, Zeng H, Zhang X, Zhao Y, Sha H, Ge X, Zhang M, Gao X, Xu Q: Phosphatase of regenerating liver-3 promotes motility and metastasis of mouse melanoma cells. Am J Pathol. 2004, 164: 2039-2054.PubMed CentralView ArticlePubMedGoogle Scholar
- Fiordalisi JJ, Keller PJ, Cox AD: PRL tyrosine phosphatases regulate rho family GTPases to promote invasion and motility. Cancer Res. 2006, 66: 3153-3161. 10.1158/0008-5472.CAN-05-3116View ArticlePubMedGoogle Scholar
- Liang F, Liang J, Wang WQ, Sun JP, Udho E, Zhang ZY: PRL3 promotes cell invasion and proliferation by down-regulation of Csk leading to Src activation. J Biol Chem. 2007, 282: 5413-5419. 10.1074/jbc.M608940200View ArticlePubMedGoogle Scholar
- Wang H, Quah SY, Dong JM, Manser E, Tang JP, Zeng Q: PRL-3 down-regulates PTEN expression and signals through PI3K to promote epithelial-mesenchymal transition. Cancer Res. 2007, 67: 2922-2926. 10.1158/0008-5472.CAN-06-3598View ArticlePubMedGoogle Scholar
- Basak S, Jacobs SB, Krieg AJ, Pathak N, Zeng Q, Kaldis P, Giaccia AJ, Attardi LD: The metastasis-associated gene Prl-3 is a p53 target involved in cell-cycle regulation. Mol Cell. 2008, 30: 303-314. 10.1016/j.molcel.2008.04.002PubMed CentralView ArticlePubMedGoogle Scholar
- Peng L, Jin G, Wang L, Guo J, Meng L, Shou C: Identification of integrin alpha1 as an interacting protein of protein tyrosine phosphatase PRL-3. Biochem Biophys Res Commun. 2006, 342: 179-183. 10.1016/j.bbrc.2006.01.102View ArticlePubMedGoogle Scholar
- Liu S, Thomas SM, Woodside DG, Rose DM, Kiosses WB, Pfaff M, Ginsberg MH: Binding of paxillin to alpha4 integrins modifies integrin-dependent biological responses. Nature. 1999, 402: 676-681. 10.1038/45264View ArticlePubMedGoogle Scholar
- Varner JA, Cheresh DA: Integrins and cancer. Curr Opin Cell Biol. 1996, 8: 724-730. 10.1016/S0955-0674(96)80115-3View ArticlePubMedGoogle Scholar
- Burridge K, Chrzanowska-Wodnicka M: Focal adhesions, contractility, and signaling. Annu Rev Cell Dev Biol. 1996, 12: 463-518. 10.1146/annurev.cellbio.12.1.463View ArticlePubMedGoogle Scholar
- Guo W, Giancotti FG: Integrin signalling during tumour progression. Nat Rev Mol Cell Biol. 2004, 5: 816-826. 10.1038/nrm1490View ArticlePubMedGoogle Scholar
- Peng L, Li Y, Meng L, Shou C: Preparation and characterization of monoclonal antibody against protein tyrosine phosphatase PRL-3. Hybrid Hybridomics. 2004, 23: 23-27. 10.1089/153685904322771999View ArticlePubMedGoogle Scholar
- Surgucheva IG, Sivak JM, Fini ME, Palazzo RE, Surguchov AP: Effect of gamma-synuclein overexpression on matrix metalloproteinases in retinoblastoma Y79 cells. Arch Biochem Biophys. 2003, 410: 167-176. 10.1016/S0003-9861(02)00664-1View ArticlePubMedGoogle Scholar
- Humphries MJ: Integrin structure. Biochem Soc Trans. 2000, 28: 311-339. 10.1042/0300-5127:0280311View ArticlePubMedGoogle Scholar
- Arao S, Masumoto A, Otsuki M: Beta1 integrins play an essential role in adhesion and invasion of pancreatic carcinoma cells. Pancreas. 2000, 20: 129-137. 10.1097/00006676-200003000-00004View ArticlePubMedGoogle Scholar
- Brakebusch C, Hirsch E, Potocnik A, Fassler R: Genetic analysis of beta1 integrin function: confirmed, new and revised roles for a crucial family of cell adhesion molecules. J Cell Sci. 1997, 110 (Pt 23): 2895-2904.PubMedGoogle Scholar
- Cheresh DA, Leng J, Klemke RL: Regulation of cell contraction and membrane ruffling by distinct signals in migratory cells. J Cell Biol. 1999, 146: 1107-1116. 10.1083/jcb.146.5.1107PubMed CentralView ArticlePubMedGoogle Scholar
- Klemke RL, Cai S, Giannini AL, Gallagher PJ, de Lanerolle P, Cheresh DA: Regulation of cell motility by mitogen-activated protein kinase. J Cell Biol. 1997, 137: 481-492. 10.1083/jcb.137.2.481PubMed CentralView ArticlePubMedGoogle Scholar
- Chang C, Werb Z: The many faces of metalloproteases: cell growth, invasion, angiogenesis and metastasis. Trends Cell Biol. 2001, 11: S37-43.PubMed CentralView ArticlePubMedGoogle Scholar
- John A, Tuszynski G: The role of matrix metalloproteinases in tumor angiogenesis and tumor metastasis. Pathol Oncol Res. 2001, 7: 14-23. 10.1007/BF03032599View ArticlePubMedGoogle Scholar
- Geiger B, Bershadsky A, Pankov R, Yamada KM: Transmembrane crosstalk between the extracellular matrix--cytoskeleton crosstalk. Nat Rev Mol Cell Biol. 2001, 2: 793-805. 10.1038/35099066View ArticlePubMedGoogle Scholar
- Howe A, Aplin AE, Alahari SK, Juliano RL: Integrin signaling and cell growth control. Curr Opin Cell Biol. 1998, 10: 220-231. 10.1016/S0955-0674(98)80144-0View ArticlePubMedGoogle Scholar
- Tan TW, Lai CH, Huang CY, Yang WH, Chen HT, Hsu HC, Fong YC, Tang CH: CTGF enhances migration and MMP-13 up-regulation via alphavbeta3 integrin, FAK, ERK, and NF-kappaB-dependent pathway in human chondrosarcoma cells. J Cell Biochem. 2009, 107: 345-356. 10.1002/jcb.22132View ArticlePubMedGoogle Scholar
- Kuo L, Chang HC, Leu TH, Maa MC, Hung WC: Src oncogene activates MMP-2 expression via the ERK/Sp1 pathway. J Cell Physiol. 2006, 207: 729-734. 10.1002/jcp.20616View ArticlePubMedGoogle Scholar
- Yoshizaki T, Sato H, Furukawa M: Recent advances in the regulation of matrix metalloproteinase 2 activation: from basic research to clinical implication (Review). Oncol Rep. 2002, 9: 607-611.PubMedGoogle Scholar
- Bode W, Fernandez-Catalan C, Grams F, Gomis-Ruth FX, Nagase H, Tschesche H, Maskos K: Insights into MMP-TIMP interactions. Ann N Y Acad Sci. 1999, 878: 73-91. 10.1111/j.1749-6632.1999.tb07675.xView ArticlePubMedGoogle Scholar
- Hunter T: Signaling--2000 and beyond. Cell. 2000, 100: 113-127. 10.1016/S0092-8674(00)81688-8View ArticlePubMedGoogle Scholar
- Neel BG, Tonks NK: Protein tyrosine phosphatases in signal transduction. Curr Opin Cell Biol. 1997, 9: 193-204. 10.1016/S0955-0674(97)80063-4View ArticlePubMedGoogle Scholar
- Ostman A, Hellberg C, Bohmer FD: Protein-tyrosine phosphatases and cancer. Nat Rev Cancer. 2006, 6: 307-320. 10.1038/nrc1837View ArticlePubMedGoogle Scholar
- Peng LR, Shou CC: [Phosphatase of regenerating liver-3 (PRL-3) and tumor metastasis]. Zhonghua Zhong Liu Za Zhi. 2007, 29: 1-3.PubMedGoogle Scholar
- Bessette DC, Wong PC, Pallen CJ: PRL-3: a metastasis-associated phosphatase in search of a function. Cells Tissues Organs. 2007, 185: 232-236. 10.1159/000101324View ArticlePubMedGoogle Scholar
- Li Z, Zhan W, Wang Z, Zhu B, He Y, Peng J, Cai S, Ma J: Inhibition of PRL-3 gene expression in gastric cancer cell line SGC7901 via microRNA suppressed reduces peritoneal metastasis. Biochem Biophys Res Commun. 2006, 348: 229-237. 10.1016/j.bbrc.2006.07.043View ArticlePubMedGoogle Scholar
- Tapley P, Horwitz A, Buck C, Duggan K, Rohrschneider L: Integrins isolated from Rous sarcoma virus-transformed chicken embryo fibroblasts. Oncogene. 1989, 4: 325-333.PubMedGoogle Scholar
- Takahashi K: The linkage between beta1 integrin and the actin cytoskeleton is differentially regulated by tyrosine and serine/threonine phosphorylation of beta1 integrin in normal and cancerous human breast cells. BMC Cell Biol. 2001, 2: 23- 10.1186/1471-2121-2-23PubMed CentralView ArticlePubMedGoogle Scholar
- Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, Nardone J, Lee K, Reeves C, Li Y: Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell. 2007, 131: 1190-1203. 10.1016/j.cell.2007.11.025View ArticlePubMedGoogle Scholar
- Schwartz MA, Assoian RK: Integrins and cell proliferation: regulation of cyclin-dependent kinases via cytoplasmic signaling pathways. J Cell Sci. 2001, 114: 2553-2560.PubMedGoogle Scholar
- Schwartz MA, Ginsberg MH: Networks and crosstalk: integrin signalling spreads. Nat Cell Biol. 2002, 4: E65-E68. 10.1038/ncb0402-e65View ArticlePubMedGoogle Scholar
- Yee KL, Weaver VM, Hammer DA: Integrin-mediated signalling through the MAP-kinase pathway. IET Systems Biology. 2008, 2: 8-15. 10.1049/iet-syb:20060058View ArticlePubMedGoogle Scholar
- Bouchard V, Harnois C, Demers MJ, Thibodeau S, Laquerre V, Gauthier R, Vezina A, Noel D, Fujita N, Tsuruo T: B1 integrin/Fak/Src signaling in intestinal epithelial crypt cell survival: integration of complex regulatory mechanisms. Apoptosis. 2008, 13: 531-542. 10.1007/s10495-008-0192-yView ArticlePubMedGoogle Scholar
- Kong L, Li Q, Wang L, Liu Z, Sun T: The value and correlation between PRL-3 expression and matrix metalloproteinase activity and expression in human gliomas. Neuropathology. 2007, 27: 516-521. 10.1111/j.1440-1789.2007.00818.xView ArticlePubMedGoogle Scholar
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