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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review GPA33 (glycoprotein A33 (transmembrane)) Tania Tabone, Joan K Heath Ludwig Institute for Cancer Research, Melbourne Branch, PO Box 2008, Royal Melbourne Hospital, Parkville, VIC 3050, Australia (TT, JKH) Published in Atlas Database: June 2008 Online updated version : http://AtlasGeneticsOncology.org/Genes/GPA33ID40735ch1q23.html DOI: 10.4267/2042/44469 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 Identity Other names: A33; MGC129986; MGC129987 HGNC (Hugo): GPA33 Location: 1q24.1 Note: Location of GPA33 on human chromosome 1q24 showing flanking genes to demonstrate synteny to other vertebrates, such as mouse (chromosome 1) and zebrafish (chromosomes 1 and 9). Note that an evolutionary duplication event of the entire zebrafish genome has resulted in the two copies of gpa33 in zebrafish. DNA/RNA Transcription Description 2,793 bp mRNA; 960 bp open reading frame (Heath et al., 1997). The human GPA33 gene comprises 7 exons (all coding) spanning 37,787 bp of genomic DNA. Atlas Genet Cytogenet Oncol Haematol. 2009; 13(5) 354 GPA33 (glycoprotein A33 (transmembrane)) Tabone T, Heath JK Genomic organization of the GPA33 gene. Coding exonic sequences appear in red, non-coding exonic sequences are in blue and intronic sequence are in yellow, with the corresponding exon and intron sizes given below in base pairs (bp). The exon numbers are indicated above each exon. Note the GPA33 gene is in on the reverse strand. Schematic representation of the GPA33 protein, indicating the position of the Ig-like V-type and Ig-like C2-type domain in the extracellular region and the polycysteine residue ('CCCC' motif). Protein Function Description Unknown; the protein structure is consistent with a putative role of GPA33 in cell-cell recognition and signaling (Heath et al., 1997). A33 may play a role in relaying information between intestinal epithelial cells and the gut immune system (Lee et al., 2007). 319 amino acids; 43 kDa protein. The A33 glycoprotein is a member of the immunoglobulin superfamily and contains three distinct structural domains: a 213 amino acid extracellular region containing two immunoglobulin-like domains (a C2type domain and a v-type domain), a 23 amino acid hydrophobic transmembrane domain, and a 62 amino acid highly polar intracellular tail containing four consecutive cysteine residues (Heath et al., 1997). Post translational modification includes N-glycosylation (containing approximately 8 kDa of N-linked carbohydrate), and S-palmitoylation. The Spalmitoylation may be involved in regulating the internalization process initiated by binding of the monoclonal antibody A33 to the A33 antigen. There is no evidence of O-glycosylation, sialylation or glycophosphatidylinositol (Ritter et al., 1997). Homology The two Ig-like domains are well conserved between humans, chimpanzee, dog, mouse and rat, whereas chicken and zebrafish retain only the Ig-like V-like domain. The overall GPA33 protein similarity between humans and various species are: chimpanzee (Pan troglodytes) 97%, domestic dog (Canis lupus familiaris) 75%, mouse (Mus musculus) 66%, rat (Rattus norvegicus) 68%, domestic chicken (Gallus gallus) 44%, and zebrafish (Danio rerio) 35%. Implicated in Colorectal cancer Expression Note Colorectal cancer marker. Although the biochemical, immunological and molecular biology of the A33 antigen has been extensively characterized, the function of the molecule remains unknown. The antigen has several identified properties that contribute to a potential therapeutic target for colon cancer. The A33 antigen is expressed homogenously and at high levels in colorectal carcinomas, there are a high number of A33 binding sites per cell and it is not shed or secreted into the blood stream (Welt et al., 1990). In addition, upon mAB binding to the A33 antigen, the antibody-antigen GPA33 demonstrates a rare tissue-specific expression pattern. GPA33 is a cell surface differentiation antigen that is constitutively expressed on the basolateral surfaces of normal human and mouse colon and small bowel epithelium. GPA33 is homogeneously expressed in over 95% of both human primary and metastatic colon cancers, and in 55% of gastric carcinomas, although absent in normal stomach epithelium (Welt et al., 1990). Localisation Membrane; single-pass type 1 membrane protein. Atlas Genet Cytogenet Oncol Haematol. 2009; 13(5) 355 GPA33 (glycoprotein A33 (transmembrane)) Tabone T, Heath JK Daghighian F, Barendswaard E, Welt S, Humm J, Scott A, Willingham MC, McGuffie E, Old LJ, Larson SM. Enhancement of radiation dose to the nucleus by vesicular internalization of iodine-125-labeled A33 monoclonal antibody. J Nucl Med. 1996 Jun;37(6):1052-7 complex is internalized and sequestered in vesicles (Daghighian et al., 1996). Selective immunological targeting of tumors with monoclonal antibodies (mAb) is an important therapeutic approach in cancer therapy. Clinical imaging and biopsy-based biodistribution studies using radiolabeled murine mAb A33 demonstrated specific targeting to antigen-positive tumor tissues in 95% of colorectal patients with tumor retention for up to six weeks (Welt et al., 1990; Welt et al., 1994). The only normal tissue reported to accumulate the radioisotope was the bowel, with clearance from the normal gastrointestinal tract within one week. Phase I and II therapy trials using 125I- and 131I-labeled murine A33 mAb were shown to have antitumor effects without bowel toxicity, however human anti-mouse antibody development in all patients prevented repeated dosing and led to the development of humanized mAb A33 (huA33). Phase I clinical trials using multiple dose schedules of 125I- and 131I-labled huA33 mAb in patients with colorectal carcinoma have been conducted and have shown safety and possible efficacy, with future trials proposed (Chong et al., 2005; Scott et al., 2005). Heath JK, White SJ, Johnstone CN, Catimel B, Simpson RJ, Moritz RL, Tu GF, Ji H, Whitehead RH, Groenen LC, Scott AM, Ritter G, Cohen L, Welt S, Old LJ, Nice EC, Burgess AW. The human A33 antigen is a transmembrane glycoprotein and a novel member of the immunoglobulin superfamily. Proc Natl Acad Sci U S A. 1997 Jan 21;94(2):469-74 Ritter G, Cohen LS, Nice EC, Catimel B, Burgess AW, Moritz RL, Ji H, Heath JK, White SJ, Welt S, Old LJ, Simpson RJ. Characterization of posttranslational modifications of human A33 antigen, a novel palmitoylated surface glycoprotein of human gastrointestinal epithelium. Biochem Biophys Res Commun. 1997 Jul 30;236(3):682-6 Chong G, Lee FT, Hopkins W, Tebbutt N, Cebon JS, Mountain AJ, Chappell B, Papenfuss A, Schleyer P, U P, Murphy R, Wirth V, Smyth FE, Potasz N, Poon A, Davis ID, Saunder T, O'keefe GJ, Burgess AW, Hoffman EW, Old LJ, Scott AM. Phase I trial of 131I-huA33 in patients with advanced colorectal carcinoma. Clin Cancer Res. 2005 Jul 1;11(13):4818-26 Scott AM, Lee FT, Jones R, Hopkins W, MacGregor D, Cebon JS, Hannah A, Chong G, U P, Papenfuss A, Rigopoulos A, Sturrock S, Murphy R, Wirth V, Murone C, Smyth FE, Knight S, Welt S, Ritter G, Richards E, Nice EC, Burgess AW, Old LJ. A phase I trial of humanized monoclonal antibody A33 in patients with colorectal carcinoma: biodistribution, pharmacokinetics, and quantitative tumor uptake. Clin Cancer Res. 2005 Jul 1;11(13):4810-7 References Welt S, Divgi CR, Real FX, Yeh SD, Garin-Chesa P, Finstad CL, Sakamoto J, Cohen A, Sigurdson ER, Kemeny N. Quantitative analysis of antibody localization in human metastatic colon cancer: a phase I study of monoclonal antibody A33. J Clin Oncol. 1990 Nov;8(11):1894-906 Lee JW, Epardaud M, Sun J, Becker JE, Cheng AC, Yonekura AR, Heath JK, Turley SJ. Peripheral antigen display by lymph node stroma promotes T cell tolerance to intestinal self. Nat Immunol. 2007 Feb;8(2):181-90 Welt S, Divgi CR, Kemeny N, Finn RD, Scott AM, Graham M, Germain JS, Richards EC, Larson SM, Oettgen HF. Phase I/II study of iodine 131-labeled monoclonal antibody A33 in patients with advanced colon cancer. J Clin Oncol. 1994 Aug;12(8):1561-71 Atlas Genet Cytogenet Oncol Haematol. 2009; 13(5) This article should be referenced as such: Tabone T, Heath JK. GPA33 (glycoprotein A33 (transmembrane)). Atlas Genet Cytogenet Oncol Haematol. 2009; 13(5):354-356. 356