Download Gene Section GPA33 (glycoprotein A33 (transmembrane)) Atlas of Genetics and Cytogenetics

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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