Phosphatase of regenerating liver-3 directly interacts with integrin β1 and regulates its phosphorylation at tyrosine 783
© Tian et al.; licensee BioMed Central Ltd. 2012
Received: 10 July 2012
Accepted: 26 September 2012
Published: 23 October 2012
Phosphatase of regenerating liver-3 (PRL-3 or PTP4A3) has been implicated in controlling cancer cell proliferation, motility, metastasis, and angiogenesis. Deregulated expression of PRL-3 is highly correlated with cancer progression and predicts poor survival. Although PRL-3 was categorized as a tyrosine phosphatase, its cellular substrates remain largely unknown.
We demonstrated that PRL-3 interacts with integrin β1 in cancer cells. Recombinant PRL-3 associates with the intracellular domain of integrin β1 in vitro. Silencing of integrin α1 enhances PRL-3-integrin β1 interaction. Furthermore, PRL-3 diminishes tyrosine phosphorylation of integrin β1 in vitro and in vivo. With site-specific anti-phosphotyrosine antibodies against residues in the intracellular domain of integrin β1, tyrosine-783, but not tyrosine-795, is shown to be dephosphorylated by PRL-3 in a catalytic activity-dependant manner. Phosphorylation of Y783 is potentiated by ablation of PRL-3 or by treatment with a chemical inhibitor of PRL-3. Conversely, depletion of integrin α1 decreases the phosphorylation of this site.
Our results revealed a direct interaction between PRL-3 and integrin β1 and characterized Y783 of integrin β1 as a bona fide substrate of PRL-3, which is negatively regulated by integrin α1.
KeywordsPRL-3 tyrosine phosphatase integrin β1 dephosphorylation
PRL-3, a non-receptor tyrosine phosphatase containing a CAAX motif for prenylation at the carboxyl terminus , was found to be up-regulated in various types of malignancy, including colorectal, gastric, ovarian and breast cancers [2–5]. It has been shown to play a causal role in tumor metastasis by enhancing cancer cell motility and in tumor angiogenesis by recruiting endothelial cells . PRL-3 expression is correlated with disease progression and poor survival [3–8], and its antibody was shown to dramatically inhibit metastatic tumor formation in human ovarian cancer cells , therefore it had been deemed as a potential therapeutic target for the treatment of cancer .
PRL-3 could down-regulate PTEN expression and activate the PI3K pathway to promote epithelial-mesenchymal transition (EMT), thus contributing to tumor metastasis . It has been implicated in controlling integrin-Src signaling pathway, in which ectopic PRL-3 promoted Src activation and potentiated Src-modulated oncogenic pathways, including ERK1/2, STAT3, and p130Cas . PRL-3 was also shown to be a negative regulator of tumor suppressor p53 . As a phosphatase, few PRL-3 substrates had been characterized, including Ezrin  and cytokeratin 8 , however, the cellular substrates of PRL-3 remain largely unknown.
Integrins are a large family of trans-membrane proteins, which are broadly involved in regulation of cell adhesion, motility and other physical and pathological processes [16, 17]. Engagement of intergrins with their ligands stimulates diverse intracellular signaling pathways, such as tyrosine phosphorylation and activation of mitogen-activated protein kinases [18, 19]. Integrin α1 and β1 are known to heterodimerize to form the receptor for extracellular matrix (ECM), which is prerequisite for downstream signaling . We previously identified integrin α1 as an interacting protein of PRL-3 through yeast two-hybrid screening, and PRL-3 could down-regulate the tyrosine-phosphorylation level of integrin β1 . Furthermore, we showed the critical role of integrin β1-ERK1/2-MMP2 signaling in PRL-3-promoted motility, invasion, and metastasis of colon cancer cells . In this study, we demonstrate that PRL-3 directly binds to integrin β1 and dephosphorylates integrin β1-Y783, a key residue for integrin β1 function . Moreover, we show that integrin α1 inhibits the PRL-3/integrin β1 interaction and the dephosphorylation of integrin β1-Y783 by PRL-3.
Direct interaction between PRL-3 and integrin β1, which is regulated by integrin α1
In vitro and in vivo dephosphorylation of integrin β1 by PRL-3
Moreover, we examined if such regulation occurs in vivo. We introduced myc-PRL-3 into BGC823 and HCT116 cells. As controls, the cells were transfected with vector alone. Immunoblot analysis revealed that ectopic expression of myc-PRL-3 considerably decreased the phosphorylation of integrin β1 at tyrosine residue(s), but did not affect total protein levels of integrin β1 (Figure 3C). These results indicate that PRL-3 dephosphorylates integrin β1 in vitro and in vivo.
PRL-3 dephosphorylates tyrosine-783 of integrin β1
Protein kinases and phosphatases play important roles in diverse physiological processes and diseases [26–28]. PRL-3, as a member of protein phosphatases, has been found to promote cancer cell invasiveness [10, 29–32]. However, the underlying mechanism remains elusive. In the present study, we demonstrate that PRL-3 directly binds to integrin β1 and dephosphorylates integrin β1-Y783. Furthermore, we found that deletion of integrin α1 resulted in increased PRL-3-integrin β1 association and decreased phosphorylation of integrin β1-Y783. These findings indicate that integrin β1 is a bona fide substrate of PRL-3 and raise the possibility that integrin α1 may function as a negative regulator for PRL-3-integrin β1 interaction.
Previous studies have shown that integrin β1-Y783 and -Y795 are parts of conserved NPxY motifs essential for recruiting talin and kindlin, which in turn facilitates coupling of integrin β1 to the actin cytoskeleton and maintains integrins in an active signaling state . It was reported that v-Src could phosphorylate integrin β1 tails on Y783 and Y795 [34, 35], and that phosphorylated Y783 and Y795 could block talin and kindlin’s binding with integrin β1, respectively [36, 37]. These were supported by the study that v-Src expression in fibroblasts decreases integrin β1–dependent adhesion, focal adhesion formation, cytoskeletal organization, fibronectin assembly, migration, and chemotaxis [34, 38]. While several kinases, including Src, have been shown to phosphorylate Y783 and Y795 [34, 35], the phosphatase(s) catalyzing the de-phosphorylation of these two sites is unknown. By showing PRL-3 is responsible for dephosphorylating pY783, our present results provide an explanation for the delicate control of integrin β1.
It is noted that a recent study showing the short phosphotyrosine peptides encompassing Y783 or Y795 of integrin β1 could not be dephosphorylated by PRL-3 in an in vitro assay . However, as the author suggested, this could be explained by lack of entire integrin β1 to be recognized by PRL-3 . In our study, instead of using the synthesized peptides, we immunoprecipited the endogenous integrin β1 as substrate for in vitro phosphatase assay, which ensures optimal phosphatase-substrate association. In addition, we did not find alteration in pY795 by over-expression or ablation of PRL-3, which could be due to the fact that pY795 level is too low to be detected in the cancer cells examined. We did observe slightly more pY795 in PRL-3 inhibitor treated BGC823 cells, while such agent-induced changes of pY795 was not as robust as those of pY783 in BGC823 and SW480 cells. Interestingly, treatment with a pan-phosphatase inhibitor significantly elevates pY795, suggesting that PRL-3 may partially contribute to the dephosphorylation of pY795 and pY795 is mainly regulated by other phosphatase(s).
In summary, our results demonstrated a direct interaction between PRL-3 and integrin β1, which could be negatively regulated by integrin α1. Importantly, we identified tyrosine 783 of integrin β1 as a direct dephosphorylation site by PRL-3, thus uncovering the first tyrosine phosphorylation site to be regulated by PRL-3 phosphatase.
Cell lines and Reagents
Colon cancer cell lines LoVo, SW480 and HCT116 were obtained from ATCC (Manassas, VA) and maintained in DMEM (Invitrogen, Carlsbad, CA). Gastric cancer cell BGC823 was maintained in RPMI-1640 medium (Invitrogen). The medium was supplemented with 10% fetal calf serum (Invitrogen). The antibodies against integrin β1 (MAB 2000), integrin α1 (MAB1973) and phosphorylated tyrosine (4G10) (16–316) were from Millipore (Billerica, MA). Anti-phosphorylated integrin β1 (Tyr783) (600601) and (Tyr795) (600501) antibodies were obtained from Biolegend (San Diego, CA). Antibody against PRL-3 (clone 318) was from Santa Cruz (Santa Cruz, CA). GADPH antibody was from Proteintech Group (Chicago, IL). PRL-3 inhibitor 1-(2-bromobenzyloxy)-4-bromo-2-benzylidene rhodanine (P0108) was from Sigma (St. Louis, MO). The tyrosine phosphatase inhibitor (Pervanadate) was freshly prepared by dissolving sodium orthovanadate (Sigma) with PBS to 30 mM, adding hydrogen peroxide at 0.18% (v/v), and incubating for 15 min at room temperature avoiding light before treating the cells at the final concentration of 100 μM.
Plasmids transfection and RNA interference
The plasmids expressing myc-PRL-3, myc-PRL-3-mt (cystine 104 was mutated to serine) and GFP-PRL-3 were described as previously . The small interference RNAs (siRNAs) targeting integrin α1 and PRL-3 were synthesized by GenePharma (Shanghai, China), the sequence for integrin α1: sense, 5’- GCCCUUAUAUGCCUAUAGA -3’; antisense, 5’- UCUAUAGGCAUAUAAGGGC -3’; the sequence for PRL-3: sense, 5’- CAGCAAGCAGCUCACCUAC -3’; antisense, 5’- GUAGGUGAGCUGCUUGCUG -3’. Plasmids and siRNA were transfected into cells with Lipofectamine 2000 (Invitrogen) following provider’s instruction.
To visualize the localization of integrin β1, BGC823 cells were cultured on the coverslips and fixed with 2% paraformaldehyde for 30 min at 4°C, followed by permeabilization with 0.5% Triton X-100 in PBS for 5 min, and blocking with 3% bovine serum albumin overnight at 4°C. After incubation with anti-integrin β1 (1: 300) for 1 hr at room temperature, cells were probed with tetramethyl rhodamine isothiocyanate-conjugated secondary antibody, counterstained with 4', 6-diamidino-2-phenylindole (DAPI), and mounted on 50% glycerol/PBS. Localization of PRL-3 was analyzed by transfecting the cells with pEGFP-PRL-3. A Leica SP2 confocal system (Leica Microsystems, Dresden, Germany) was used to observe the localization of integrin β1 and GFP-PRL-3.
Western blotting and immunoprecipitation
For Western blotting, cells were directly lysed in 1x loading buffer. For immunoprecipitation assay, cells were homogenized in lysis buffer (50 mM HEPES pH 8.0, 150 mM NaCl, 1 mM EDTA, 1% Triton X-100, 10% glycerol, 50 mM NaF, 1 mM Na3VO4, 2 mM dithiothreitol, 1 × protease cocktail (Sigma)) for 20 min at 4°C. The supernatant was collected after centrifugation at 12,000 × g for 20 min at 4°C and then incubated with indicated antibodies conjugated to protein G-Sepharose (Invitrogen). Cell lysates or immunoprecipitates were separated by SDS-PAGE and electro-blotted to the nitrocellulose membranes. Non-specific binding was blocked with 5% non-fat milk in PBS overnight at 4°C and was rinsed twice with PBST. Then the membranes were incubated with indicated primary antibodies at room temperature for 1.5 h, and washed six times with PBST, followed by horseradish peroxidase-labeled secondary antibodies for 45 min and washed again as above. Protein bands were visualized with enhanced chemoluminescence system (Thermo Scientific, Rockford, IL).
GST Pull-down assay
Deoxyribonucleic acids encoding intracellular domain of integrin β1 (752-798aa) was amplified by PCR with the following primers: sense, 5’- GACTGAATTCAAGCTTTTAATGATAATTCATG -3’; antisense, 5’- AGCAACTCGAGGTGTTGTGGGATTTGCAC -3’. The PCR product was digested by EcoR I/Xho I and inserted into pGEX-4T1 vector. His-tagged PRL-3 was constructed by inserting the digested PRL-3 into pET-28a vector. For pull-down assay, glutathione-Sepharose beads (Invitrogen) were incubated with E. coli bacteria lysates expressing GST-integrin β1 or GST. After being washed with PBS, these beads were incubated with His-PRL-3 in binding buffer (10 mM Tris–HCl pH 8.0, 150 mM NaCl, 1 mM dithiothreitol, 1 mM PMSF, 1% Triton X-100, 10% glycerol) for 4 hours at 4°C, then washed three times, boiled in SDS loading buffer, separated by SDS-PAGE and immunoblotted with PRL-3 and GST antibodies.
In vitro phosphatase assay
Integrin β1 protein was immunoprecipitated from 1000 μg protein from HCT116 cell lysates with 1 μg integrin β1 antibody conjugated to protein G-Sepharose. For control, cell lysates were immunoprecipitated with 1 μg pre-immune IgG. After being washed 3 times with lysis buffer, once with dephosphorylation buffer (50 mM Tris pH 7.5, 2 mM dithiothreitol, 1 mM MgCl2, 0.1 mM MnCl2), the precipitates were used as substrate for in vitro phosphatase assay. GST-PRL-3, GST-PRL-3-mt, and GST (1 μg each) were used as phosphatase and incubated with substrate in 20 μL dephosphorylation buffer at 30°C for 30 min. The reaction was stopped by boiling in 2 × loading buffer and the phosphorylated integrin β1 was detected by immunoblotting with 4G10 antibody.
Phosphatase of regenerating liver-3
Sodium dodecyl sulfate polyacrylamide gel electrophoresis
Small interference RNA
We deeply appreciate Dr. Jin Q. Cheng and Dr. Jianping Guo (H. Lee Moffitt Cancer Center and Research Institute, USA) for their generous help in the study and critical comments on the manuscript. We also appreciate Dr. Qi Zeng (Institute of Molecular and Cell Biology, Singapore) and Dr. Jianming Li (Southern Medical University, China) for helpful discussion and sharing unpublished data. This study was supported by the National Natural Science Foundation of China (81071732, 30973407) and National 973 Program of China (2009CB521805). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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