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Review Article XB130—A Novel Adaptor Protein: Gene, Function, and Roles in Tumorigenesis

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Review Article XB130—A Novel Adaptor Protein: Gene, Function, and Roles in Tumorigenesis Hindawi Publishing Corporation Scientifica Volume 2014, Article ID 903014, 9 pages http://dx.doi.org/10.1155/2014/903014 Review Article XB130—A Novel Adaptor Protein: Gene, Function, and Roles in Tumorigenesis Xiao-Hui Bai,1 Hae-Ra Cho,1,2 Serisha Moodley,1,3 and Mingyao Liu1,2,3,4 1 Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network, 101 College Street, Toronto,ON,CanadaM5G1L7 2 Department of Physiology, Faculty of Medicine, University of Toronto, 1 King’s College Circle, Toronto,ON,CanadaM5S1A8 3 Institute of Medical Science, Faculty of Medicine, University of Toronto, 1 King’s College Circle, Toronto, ON, Canada M5S 1A8 4 Department of Surgery, Faculty of Medicine, University of Toronto, 149 College Street, Toronto, ON, Canada M5T 1P5 Correspondence should be addressed to Mingyao Liu; [email protected] Received 10 February 2014; Accepted 15 May 2014; Published 5 June 2014 Academic Editor: Patrick Auberger Copyright © 2014 Xiao-Hui Bai et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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 thep85 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. 1. Introduction 2. XB130: A Novel Gene and Protein All cellular functions are regulated through various signaling XB130 was first discovered in our research group and has, pathways and protein networks. Accumulating evidence sug- subsequently, been studied by several other research groups geststhatadaptorproteins,whichcontainmultipleprotein, and scientific consortia to produce a substantial amount of lipid, and DNA interaction domains and motifs, play essen- information related to XB130 gene structure, variations, and tial roles in mediating signal transduction cascades [1, 2]. tissue distribution, which is openly available to the scientific Adaptor proteins influence cell proliferation, cell survival, community. and migration through specific protein-protein and protein- lipid interactions [3]. In this review, we will define the gene 2.1. XB130 Gene Information. XB130 was discovered through andproteinstructureofthenoveladaptorprotein,XB130,and a molecular cloning process of actin filament associated illustrate its role in cellular function and human cancers. We protein 1 (AFAP1), and its apparent molecular size is of hope to draw more attention to this signaling molecule and 130 kDa [4]. XB130 is also known as actin filament asso- use it as an example to promote scientific awareness about ciated protein 1-like 2 (AFAP1L2) [5], KIAA1914 [6], and the importance of adaptor proteins in signal transduction. PI3KAP [7]. The human xb130 gene (NCBI gene ID 84632; 2 Scientifica c-Src binding and activation p85 binding Lamellipodia Lamellipodia translocation Lipid binding translocation 1 PH PH Unique region Coiled-coil 818 175–271 353–446 491–648 652–750 757–818 54YIYM57124YEEA127 457YDYV460 148YDEE151 98PDLPPPKMIP107 Proline-rich domain Figure 1: XB130 functional domains and motifs. The N-terminus of XB130 contains a proline-rich SH3 domain binding motif at aa 98–107 and three tyrosine containing SH2 domain binding sites at aa 54–57, aa 124–127, and aa 148–15. The first SH2 domain binding site contains a YXXM motif that binds the SH2 domain in the p85 subunit of PI3K. In the middle region, there are two PH domains and another SH2 domain binding site at aa 457–460. The C-terminus contains a coiled-coil region. Unigene cluster Hs.591106; Hugo gene ID 25901; Swiss- by Illumina Body Map also shows expression in lymph node, Port ID Q8N4X5) is located on chromosome 10 at 10q25.3 adipocytes, adrenal gland, breast, ovary, prostate, and testis between nucleotide positions 116,054,583 and 116,164,515 (http://www.genecard.org/)[8]. The expression of XB130 (http://www.genecards.org/)[8]. Neighboring genes are protein has also been confirmed with immunohistochemistry NHLRC2, TDRD1 (encodes a scaffold protein), VWA2 staining in human thyroid [14], submucosal glands of esoph- (involved in cytoskeleton structure stabilization), ADRB1, agus [15], and stomach [16]. ABLIM1, and PPIAP19. The proteins, von Willebrand factor A domain containing 2 (VWA2)and actin-binding LIM protein 1 (ABLIM1), are scaffold-like proteins with putative functions 2.2. XB130: A Member of AFAP Family. Like many other in cytoskeleton structural stabilization or remodeling [9, 10]. discoveries in science, XB130 was discovered serendipitously, In addition, at least 10 small nuclear polymorphisms (SNPs) while attempting to clone the human AFAP1 gene [4]. are present in the xb130 genome (http://www.genecards.org), Using the chicken AFAP1 cDNA sequence as a search query, which may relate to tissue specificity, genetically heritable XB130 was found in the human EST clone library (GenBank disease association, or cancer formation and development. accession 1154093) and showed 40% sequence homology with The human xb130 gene has 19 exons that cover the whole chicken and human AFAP1. Due to XB130’s sequence and coding sequence. Putative homologs of XB130 have been structural similarities to AFAP1, XB130 belongs to the AFAP identified from chimpanzee, mouse, rat, bovine, chicken, and family of proteins. zebra fish. The AFAP family contains three members; AFAP1, The transcript size of human xb130 is 3,751 bp in length AFAP1L1, and XB130 (AFAP1L2). All AFAP family members and encodes an 818-amino-acid protein [4]. The molecular contain two PH domains and a number of SH2 and SH3 weight of this protein by western blot analysis is approxi- binding domain motifs [5]. However, the number and loca- mately 130 kDa [4]. Furthermore, there are seven putative tion of SH2 and SH3 binding domain motifs, as well as other splicing variants based on Ensembl sequence alignment unique domains and sequences, differ in each AFAP family ENSG00000169129 [11]. XB130 also contains several tyrosine member (Figure 2). For example, AFAP1 has two SH3 binding phosphorylation sites and a proline-rich region (PRR) at motifs at the N-terminus, while AFAP1L1 and XB130 have the N-terminus, which allows XB130 to interact with Src only one SH3 binding motif [4, 5, 17]. AFAP1 and AFAP1L1 Homology 2 (SH2) and Src Homology 3 (SH3) domain have one SH2 binding motif, whereas XB130 has three at containing proteins, respectively [4]. In addition, there are the N-terminus. The C-termini of AFAP family members two pleckstrin-homology (PH) sequences located in the bear more functional differences. For instance, AFAP1 and middleoftheprotein,whichareputativephospholipid AFAP1L1 contain a leucine zipper and an actin-binding and/or membrane binding domains of XB130. Lastly, a domain (ABD), whereas XB130 only contains a coiled-coil coiled-coil domain is located at the C-terminal of XB130, domain in this region (Figure 2)[5]. The unique structural which may be involved in XB130 protein dimerization properties and arrangement of these proteins establish their (Figure 1). localization in different cellular compartments and deter- XB130 mRNA is highly expressed in human thyroid and mine their binding affinities and interactions with different spleen and moderately expressed in other organs, such as molecules that are involved in several signaling pathways that brain, pancreas, lung, and kidney [12]. According to the influence different cellular functions. For instance, AFAP1 HumanProteinAtlasdatabase,XB130proteinispresentin has a strong association with filamentous actin stress fibers thyroid, parathyroid, brain, kidney, skin, and gastrointesti- involved in cytoskeletal remodeling, focal adhesion forma- nal tracks, which include esophagus, stomach, and colon tion, and mechanotransduction [17, 18]. AFAP1L1 localizes (http://www.proteinatlas.org/)[13]. RNA sequence analysis at the cell periphery in cytoskeletal outgrowths, known as Scientifica 3 AFAP1 1 PH PH Leucine zipper ABD 730 AFAP1L1 1 PH PH Leucine zipper ABD 768 XB130/ 1 Unique region AFAP1L2 PH PH Coiled-coil 818 Figure 2: AFAP family proteins. XB130 shares both sequence and structural similarities to the AFAP family of proteins. GSTSrc GAP Grb2 Nckp85 PLC Shc WCL and in vitro [4]. XB130 also binds to the SH2 domain of Lck XB130- kinase, which is expressed in colorectal cancer cells [22]. Using the GST-fusion protein pull-down assay, it has been shown that XB130 binds SH2 domain containing proteins, such
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