XB130 Mediates Cancer Cell Proliferation and Survival through Multiple Signaling Events Downstream of Akt

Hungarian Academy of Sciences, Hungary
PLoS ONE (Impact Factor: 3.23). 08/2012; 7(8):e43646. DOI: 10.1371/journal.pone.0043646
Source: PubMed


XB130, a novel adaptor protein, mediates RET/PTC chromosome rearrangement-related thyroid cancer cell proliferation and survival through phosphatidyl-inositol-3-kinase (PI3K)/Akt pathway. Recently, XB130 was found in different cancer cells in the absence of RET/PTC. To determine whether RET/PTC is required of XB130-related cancer cell proliferation and survival, WRO thyroid cancer cells (with RET/PTC mutation) and A549 lung cancer cells (without RET/PTC) were treated with XB130 siRNA, and multiple Akt down-stream signals were examined. Knocking-down of XB130 inhibited G(1)-S phase progression, and induced spontaneous apoptosis and enhanced intrinsic and extrinsic apoptotic stimulus-induced cell death. Knocking-down of XB130 reduced phosphorylation of p21Cip1/WAF1, p27Kip1, FOXO3a and GSK3β, increased p21Cip1/WAF1protein levels and cleavages of caspase-8 and-9. However, the phosphorylation of FOXO1 and the protein levels of p53 were not affected by XB130 siRNA. We also found XB130 can be phosphorylated by multiple protein tyrosine kinases. These results indicate that XB130 is a substrate of multiple protein tyrosine kinases, and it can regulate cell proliferation and survival through modulating selected down-stream signals of PI3K/Akt pathway. XB130 could be involved in growth and survival of different cancer cells.


Available from: Valentina De Falco, May 26, 2014
  • Source
    • "XB130 (also called AFAP1L2, for actin filament associated protein 1 like 2) is a newly discovered adaptor protein [13]. XB130 is involved in the regulation of cell proliferation, survival and migration, through its binding with p85α, the regulatory subunit of PI3K, and subsequent activation of PI3K/Akt related signaling[14]–[16]. Microarray and bioinformatics studies have shown that stably knockdown Xb130 using shRNA significantly changed multiple gene expression [15]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The repair and regeneration of airway epithelium is important for maintaining homeostasis of the respiratory system. XB130 is an adaptor protein involved in the regulation of cell proliferation, survival and migration. In the human trachea, XB130 is expressed on the apical site of ciliated epithelial cells. We hypothesize that XB130 may play a role in epithelial repair and regeneration after injury. Xb130 knockout (KO) mice were generated, and a mouse isogenic tracheal transplantation model was used. Adult Xb130 KO mice did not show any significant anatomical and physiological phenotypes in comparison with their wild type (WT) littermates. The tracheal epithelium in Xb130 KO mice, however, was significantly thicker than that in WT mice. Severe ischemic epithelial injury was observed immediately after the tracheal transplantation, which was followed by epithelial cell flattening, proliferation and differentiation. No significant differences were observed in terms of initial airway injury and apoptosis. However, at Day 10 after transplantation, the epithelial layer was significantly thicker in Xb130 KO mice, and associated with greater proliferative (Ki67+) and basal (CK5+) cells, as well as thickening of the connective tissue and fibroblast layer between the epithelium and tracheal cartilages. These results suggest that XB130 is involved in the regulation of airway epithelial differentiation, especially during airway repair after injury.
    PLoS ONE 10/2014; 9(10):e108952. DOI:10.1371/journal.pone.0108952 · 3.23 Impact Factor
  • Source
    • "Adaptor proteins are essential in the maintenance of normal cellular physiology and homeostasis by acting as scaffolds and transmitters that bind and translocate molecules to larger complexes or cellular compartments to aid in signal transduction. By acting as an upstream regulator of PI3K, XB130 plays an important role in mediating cell survival and proliferation through Akt pathways [21] and in cell migration through Rac-dependent pathways [12, 19]. The role of XB130 is not limited to protein activity and several studies have shown that XB130 also participates in the regulation of gene expression [14] (Figure 4). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Several adaptor proteins have previously been shown to play an important role in the promotion of tumourigenesis. XB130 (AFAP1L2) is an adaptor protein involved in many cellular functions, such as cell survival, cell proliferation, migration, and gene and miRNA expression. XB130's functional domains and motifs enable its interaction with a multitude of proteins involved in several different signaling pathways. As a tyrosine kinase substrate, tyrosine phosphorylated XB130 associates with the p85 α regulatory subunit of phosphoinositol-3-kinase (PI3K) and subsequently affects Akt activity and its downstream signalling. Tumourigenesis studies show that downregulation of XB130 expression by RNAi inhibits tumor growth in mouse xenograft models. Furthermore, XB130 affects tumor oncogenicity by regulating the expression of specific tumour suppressing miRNAs. The expression level and pattern of XB130 has been studied in various human tumors, such as thyroid, esophageal, and gastric cancers, as well as, soft tissue tumors. Studies show the significant effects of XB130 in tumourigenesis and suggest its potential as a diagnostic biomarker and therapeutic target for cancer treatments.
    06/2014; 2014:903014. DOI:10.1155/2014/903014
  • Source
    • "Several signaling pathways are involved in this process, including those mediated by focal adhesion kinase (FAK)/Src, phosphatidyl inositol 3-kinase (PI3K)/Akt, and mitogen-activated protein kinase (MAPK) [7-9]. It has been showed that XB130 is involved in the activation of Akt [10,11], while Xu et al. demonstrated that XB130 participates in activation of the c-Src pathway [1]. Intriguingly, these signaling pathways have been reported to play an essential role in the development and progression of GC [12-14], suggesting that XB130 could also be a pro-metastatic factor for GC. "
    [Show abstract] [Hide abstract]
    ABSTRACT: XB130 has been reported to be expressed by various types of cells such as thyroid cancer and esophageal cancer cells, and it promotes the proliferation and invasion of thyroid cancer cells. Our previous study demonstrated that XB130 is also expressed in gastric cancer (GC), and that its expression is associated with the prognosis, but the role of XB130 in GC has not been well characterized. In this study, we investigated the influence of XB130 on gastric tumorigenesis and metastasis in vivo and in vitro using the MTT assay, clonogenic assay, BrdU incorporation assay, 3D culture, immunohistochemistry and immunofluorescence. Western blot analysis was also performed to identify the potential mechanisms involved. The proliferation, migration, and invasion of SGC7901 and MNK45 gastric adenocarcinoma cell lines were all significantly inhibited by knockdown of XB130 using small hairpin RNA. In a xenograft model, tumor growth was markedly inhibited after shXB130-transfected GC cells were implanted into nude mice. After XB130 knockdown, GC cells showed a more epithelial-like phenotype, suggesting an inhibition of the epithelial-mesenchymal transition (EMT) process. In addition, silencing of XB130 reduced the expression of p-Akt/Akt, upregulated expression of epithelial markers including E-cadherin, alpha-catenin and beta-catenin, and downregulated mesenchymal markers including fibronectin and vimentin. Expression of oncoproteins related to tumor metastasis, such as MMP2, MMP9, and CD44, was also significantly reduced. These findings indicate that XB130 enhances cell motility and invasiveness by modulating the EMT-like process, while silencing XB130 in GC suppresses tumorigenesis and metastasis, suggesting that it may be a potential therapeutic target.
    Journal of Translational Medicine 01/2014; 12(1):1. DOI:10.1186/1479-5876-12-1 · 3.93 Impact Factor
Show more