XB130, a Novel Adaptor Protein for Signal Transduction

Division of Cellular and Molecular Biology, University Health Network Toronto General Research Institute, and Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada.
Journal of Biological Chemistry (Impact Factor: 4.57). 07/2007; 282(22):16401-12. DOI: 10.1074/jbc.M701684200
Source: PubMed


Adaptor proteins are important mediators in signal transduction. In the present study, we report the cloning and characterization of a novel adaptor protein, XB130. This gene is located on human chromosome 10q25.3 and encodes a protein of 818 amino acids. It contains several Src homology (SH)2- and SH3-binding motifs, two pleckstrin homology domains, a coiled-coil region, and a number of potential tyrosine or serine/threonine phosphorylation sites. Endogenous XB130 interacts with c-Src tyrosine kinase. Their co-expression in COS-7 cells resulted in activation of c-Src and elevated tyrosine phosphorylation of multiple proteins, including XB130 itself. XB130 expression in HEK293 cells enhanced serum response element- and AP-1-dependent transcriptional activation mediated by c-Src. XB130DeltaN, an N-terminal deletion mutant lacking a putative SH3-binding motif and several putative SH2-binding sites, reduced its ability to mediate Src signal transduction. Down-regulation of endogenous XB130 with siRNA reduced c-Src activity, IL-8 production, EGF-induced phosphorylation of Akt and GSK3beta, and altered cell cycles in human lung epithelial cells. These data suggest that XB130 as an adaptor may play an important role in the regulation of signal transduction and cellular functions.

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    • "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]. "
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    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
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    • "Furthermore, there are seven putative splicing variants based on Ensembl sequence alignment ENSG00000169129 [11]. XB130 also contains several tyrosine phosphorylation sites and a proline-rich region (PRR) at the N-terminus, which allows XB130 to interact with Src Homology 2 (SH2) and Src Homology 3 (SH3) domain containing proteins, respectively [4]. In addition, there are two pleckstrin-homology (PH) sequences located in the middle of the protein, which are putative phospholipid and/or membrane binding domains of XB130. "
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    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
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    • "XB130 is a newly discovered adaptor protein for intracellular signal transduction; it is involved in gene regulation, cell proliferation, cell survival, cell migration, and tumorigenesis [8]. XB130 is strongly expressed in the spleen and thyroid of humans, while it shows weak expression in the kidney, brain, lung, and pancreas [9]. XB130 has been detected in follicular and papillary thyroid carcinoma, human lung carcinoma cell lines [10], human oesophageal squamous cell carcinoma [11], hepatocellular carcinoma [12] as well as in gastric cancer [13]. "
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    ABSTRACT: XB130 is a newly discovered adaptor protein for intracellular signal transduction; it is involved in gene regulation, cell proliferation, cell survival, cell migration, and tumorigenesis. However, its expression and role in pancreatic ductal adenocarcinoma (PDAC) have not been investigated. The present study was designed to clarify the prognostic significance of XB130 expression in PDAC. A total of 76 consecutive patients with surgically resected PDAC were retrospectively reviewed. XB130 expression was detected by immunohistochemical analysis on the paraffin-embedded tumour sections. Correlation between the expression of XB130 and clinicopathological parameters was analyzed. XB130 expression was significantly upregulated in PDAC(56.5%, 43/76) compared to normal pancreas (0%, 0/15; P < 0.05). Increased XB130 expression was correlated with lymph node metastasis (P = 0.017), distant metastasis (P = 0.0024), high tumour-node-metastasis (TNM) stage (P =0.001), and high tumour grade (P = 0.013). The survival of 43 patients with high XB130 expression was significantly worse than that of the 33 patients with low XB130 expression (P = 0.001). Univariate analysis showed that high XB130 expression (P = 0.0045), tumour size (P = 0.024), distant metastasis (P = 0.003), TNM stage (P = 0.002) and lymphatic metastasis (P = 0.016) were independent prognostic factors of postoperative survival. Multivariate analysis using the Cox proportional hazards model showed that high XB130 expression and distant metastasis (P = 0.0239) were significant independent risk factors CONCLUSIONS: XB130 was overexpressed in the PDAC. XB130 is a promising pathological marker for the prediction of outcome in patients with PDAC.
    World Journal of Surgical Oncology 03/2014; 12(1):49. DOI:10.1186/1477-7819-12-49 · 1.41 Impact Factor
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