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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review LYPD3 (LY6/PLAUR domain containing 3) Benedikte Jacobsen, Michael Ploug Finsen Laboratory 3735, Rigshospitalet, Copenhagen Biocenter, 2200 Copenhagen N, Denmark (BJ, MP) Published in Atlas Database: October 2008 Online updated version : http://AtlasGeneticsOncology.org/Genes/LYPD3ID44245ch19q13.html DOI: 10.4267/2042/44557 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2009 Atlas of Genetics and Cytogenetics in Oncology and Haematology urokinase-type plasminogen activator receptor (uPAR) gene, in a cluster encompassing all presently known glycosylphosphatidylinositol (GPI)-anchored, multidomain proteins of the Ly6/uPAR/alpha-neurotoxin (LU) domain family. Identity Other names: C4.4A, MIG-C4 HGNC (Hugo): LYPD3 Location: 19q13.31 Description DNA/RNA 4870 bp; 5 exons (Figure 1). Transcription Note The gene for human C4.4A is located on chromosome 19q13, only 180 kb apart from the Transcription of the C4.4A gene is regulated by the transcription factor C/EBPbeta (Fries et al., 2007). Figure 1: Position of the C4.4A gene in the uPAR-like gene cluster on chromosome 19q13. The intron-exon organisation of the C4.4A gene reveals that separate exons encode the two LU domains of C4.4A, each of them with an internal phase-1 intron at loop 2, which in the three-finger LU fold is surface-exposed. Atlas Genet Cytogenet Oncol Haematol. 2009; 13(9) 647 LYPD3 (LY6/PLAUR domain containing 3) Jacobsen B, Ploug M terminal and a C-terminal signal sequence for GPI anchorage (38 residues) that are cleaved posttranslationally, yielding a mature protein of 278 residues, anchored to the cell membrane via GPI (Figure 2A). It contains two LU domains (domains I and II), each of about 90 amino acids, and a serine-, threonine-, proline-rich (STP-rich) region. LU domains adopt a "three-fingered" folding topology, that is characterized by 4 consensus disulfide bonds and an invariant C-terminal asparagine (Figure 2B). Intriguingly, domain I of C4.4A lacks one consensus cysteine bond, which is crucial to the proper folding of the single domain LU proteins. The STP-rich region is highly O-glycosylated, with 17 potential Oglycosylation sites. None of the 6 potential Nglycosylation sites of C4.4A are, however, located in this region. Differential degrees of glycosylation can probably explain the large variation in molecular weight observed in C4.4A from different sources (Hansen et al., 2004), deviating from the theoretical value of 36 kDa. Protein Note C4.4A is a GPI-anchored, multi-domain member of the Ly6/uPAR/alpha-neurotoxin (LU) protein domain family. C4.4A was identified by two independent groups seeking to identify cancer-related genes, the first observing that C4.4A was expressed in a metastasizing rat pancreatic adenocarcinoma cell line, but not on its non-metastasizing counterpart (Matzku et al., 1989), and the second showing the upregulation of C4.4A in an in vitro model system for wound healing in the urothelium, mimicking the progression of urothelial cancer (Smith et al., 2001). These findings suggested a putative role of C4.4A in cancer invasion and metastasis. Description C4.4A consists of 346 amino acid residues, including a 30 residues signal peptide at the N- Figure 2: Protein structure of C4.4A. A - Structural representation of the two LU domains and the STP-rich region of C4.4A (modified from Hansen et al., 2004). Insert: Ribbon diagram of the three-finger fold of a single LU domain (made in PyMOL™(DeLano Scientific), using PDB coordinates 1NEA). B - Disulfide connectivity in C4.4A, with LU consensus cysteine bonds highlighted in yellow. Atlas Genet Cytogenet Oncol Haematol. 2009; 13(9) 648 LYPD3 (LY6/PLAUR domain containing 3) Jacobsen B, Ploug M primarily squamous cell carcinomas (SCC) and only to a lesser extent in adenocarcinomas (AC) (Wang et al., 2006), as demonstrated in non-small cell lung cancer (NSCLC) (Figure 3D) (Hansen et al., 2007). In esophageal squamous cell carcinomas (ESCC), C4.4A expression as present in the normal mucosa is lost upon transition to dysplasia and carcinoma in situ, but reappears at the invasive front of the tumour and in lymph node metastases (Figure 3B) (Hansen et al., 2008). Expression C4.4A is expressed in the suprabasal cells of squamous epithelia found in e.g. esophagus and skin, the basal layer being devoid of C4.4A (Figure 3A), and in the amnion membrane in human term placenta (Figure 3C) (Hansen et al., 2004). In mouse skin wound healing, which is a tissue remodelling process often used as a surrogate model for cancer invasion, C4.4A is upregulated by the migrating keratinocytes. C4.4A expression is also increased in phorbolester-induced hyperplasia of murine skin (Hansen et al., 2004), in the progression to melanoma (Seiter et al., 2001) and in urothelial transitional cell carcinomas (Smith et al., 2001). The preferential expression of C4.4A in normal epithelia of the squamous type is paralleled in cancer, where it is expressed in the tumour component of Localisation C4.4A is tethered to the cell membrane via a GPIanchor, but can under certain conditions also be found intracellularly. A soluble fragment of C4.4A, termed C4.4A', resulting from cleavage in the proteasesensitive region between domain II and the STP-rich region, releasing the two N-terminal LU Figure 3: Expression of C4.4A in normal and malignant human tissue. Staining of human tissue sections with a polyclonal rabbit anti-C4.4A antibody produced at the Finsen Laboratory (Copenhagen, Denmark). C4.4A-negative basal cells are indicated by an arrow in panels A and B. (A and B, reproduced from Hansen et al., 2008; C and D, from Jacobsen, unpublished). Atlas Genet Cytogenet Oncol Haematol. 2009; 13(9) 649 LYPD3 (LY6/PLAUR domain containing 3) Jacobsen B, Ploug M domains, has been described in esophageal tissue (Hansen et al., 2008). Function Structural homology of C4.4A to the urokinase receptor, uPAR, is not reflected at the functional level, the function of C4.4A still being unknown. Circumstancial evidence, nevertheless, points to a role of C4.4A in the modulation of cell/cell and/or cell/matrix interactions: 1) The carbohydrate-binding protein galectin-3, which has been reported to be involved in cell/cell interactions, cell adhesion, migration, invasion and metastasis, has been identified as a ligand for C4.4A (Paret et al., 2005). 2) C4.4A and the cell adhesion molecule E-cadherin are co-expressed in the normal esophageal mucosa, and both are down-regulated in the progression to dysplasia (Hansen et al., 2008). 3) C4.4A-positive and not C4.4A-negative tumour cells are capable of penetrating a matrigel, and this process can be inhibited by a monoclonal anti-C4.4A antibody (Rosel et al., 1998). 4) Encapsulation of lung metastases in rats, arising after an intrafootpad injection with pancreatic tumour cells, disappears, when these tumour cells are transfected with C4.4A (Rosel et al., 1998). 5) C4.4A has recently been reported to be a novel substrate for the extracellular matrix-degrading metalloproteases ADAM10 and ADAM17 (A Disintegrin And Metalloprotease domain), which have been implicated in cell migration and proliferation, with a bearing on tumour invasion and metastasis (Esselens et al., 2008). Figure 4: Impact of C4.4A on the prognosis of NSCLC patients. Kaplan-Meier survival curves for 104 patients with NSCLC (A) and the histological subgroup with adenocarcinomas (B), stratified by expression levels of C4.4A (modified from Hansen et al., 2007, with permission). Esophageal squamous cell carcinoma (ESCC) Homology C4.4A shows homology to uPAR and other multidomain proteins of the Ly6/uPAR/alpha-neurotoxin protein domain family (PRV-1/CD177, TEX101, PRO4356, GPQH2552). Note C4.4A is absent in dysplastic esophageal epithelium as well as in early invasive ESCC, but shows a pronounced expression at the invasive front of the tumour deeper in the esophageal wall and in lymph node metastases, making C4.4A a possible new histological marker of invasion and metastasis in human ESCC (Hansen et al., 2008). Implicated in Non-small cell lung cancer (NSCLC) Disease In an immunohistochemical study encompassing 104 patients with NSCLC, high levels of C4.4A were found in 77% of SCC and in 24% of AC (Hansen et al., 2007). Preliminary data on the expression of C4.4A in premalignant lesions of NSCLC indicate that C4.4A is present already at very early stages of lung cancer progression. Prognosis A high level of C4.4A in NSCLC tissue correlates to a poorer survival of the patients (Figure 4). In the abovementioned study, it was shown that this correlation primarily could be ascribed to a dramatic effect on the patients with AC and C4.4A levels above the median, all dying within 2 years (Hansen et al., 2007). Atlas Genet Cytogenet Oncol Haematol. 2009; 13(9) References Matzku S, Wenzel A, Liu S, Zöller M. Antigenic differences between metastatic and nonmetastatic BSp73 rat tumor variants characterized by monoclonal antibodies. Cancer Res. 1989 Mar 1;49(5):1294-9 Claas C, Herrmann K, Matzku S, Möller P, Zöller M. Developmentally regulated expression of metastasisassociated antigens in the rat. Cell Growth Differ. 1996 May;7(5):663-78 Rösel M, Claas C, Seiter S, Herlevsen M, Zöller M. Cloning and functional characterization of a new phosphatidyl-inositol anchored molecule of a metastasizing rat pancreatic tumor. Oncogene. 1998 Oct 15;17(15):1989-2002 650 LYPD3 (LY6/PLAUR domain containing 3) Jacobsen B, Ploug M Seiter S, Stassar M, Rappl G, Reinhold U, Tilgen W, Zöller M. Upregulation of C4.4A expression during progression of melanoma. J Invest Dermatol. 2001 Feb;116(2):344-7 Fries F, Nazarenko I, Hess J, Claas A, Angel P, Zöller M. CEBPbeta, JunD and c-Jun contribute to the transcriptional activation of the metastasis-associated C4.4A gene. Int J Cancer. 2007 May 15;120(10):2135-47 Smith BA, Kennedy WJ, Harnden P, Selby PJ, Trejdosiewicz LK, Southgate J. Identification of genes involved in human urothelial cell-matrix interactions: implications for the progression pathways of malignant urothelium. Cancer Res. 2001 Feb 15;61(4):1678-85 Hansen LV, Skov BG, Ploug M, Pappot H. Tumour cell expression of C4.4A, a structural homologue of the urokinase receptor, correlates with poor prognosis in non-small cell lung cancer. Lung Cancer. 2007 Nov;58(2):260-6 Würfel J, Seiter S, Stassar M, Claas A, Kläs R, Rösel M, Marhaba R, Savelyeva L, Schwab M, Matzku S, Zöller M. Cloning of the human homologue of the metastasis-associated rat C4.4A. Gene. 2001 Jan 10;262(1-2):35-41 Esselens CW, Malapeira J, Colome N, Moss M, Canals F, Arribas J.. Metastasis-associated C4.4A, a GPI-anchored protein cleaved by ADAM10 and ADAM17. Biol Chem. 2008 Aug;389(8):1075-84. Hansen LV, Gårdsvoll H, Nielsen BS, Lund LR, Danø K, Jensen ON, Ploug M. Structural analysis and tissue localization of human C4.4A: a protein homologue of the urokinase receptor. Biochem J. 2004 Jun 15;380(Pt 3):845-57 Hansen LV, Laerum OD, Illemann M, Nielsen BS, Ploug M. Altered expression of the urokinase receptor homologue, C4.4A, in invasive areas of human esophageal squamous cell carcinoma. Int J Cancer. 2008 Feb 15;122(4):734-41 Paret C, Bourouba M, Beer A, Miyazaki K, Schnölzer M, Fiedler S, Zöller M. Ly6 family member C4.4A binds laminins 1 and 5, associates with galectin-3 and supports cell migration. Int J Cancer. 2005 Jul 10;115(5):724-33 Jacobsen B, Ploug M. The urokinase receptor and its structural homologue C4.4A in human cancer: expression, prognosis and pharmacological inhibition. Curr Med Chem. 2008;15(25):255973 Wang W, Ding YQ, Li ZG, Han HX, Yang L. [Expression and diagnostic application of C4.4A protein in squamous cell carcinoma and adenocarcinoma]. Zhonghua Bing Li Xue Za Zhi. 2006 May;35(5):277-80 This article should be referenced as such: Atlas Genet Cytogenet Oncol Haematol. 2009; 13(9) Jacobsen B, Ploug M. LYPD3 (LY6/PLAUR domain containing 3). Atlas Genet Cytogenet Oncol Haematol. 2009; 13(9):647651. 651