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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)
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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)
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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)
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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)
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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