Biomedical Engineering Reference
In-Depth Information
folate hydrolyse in prostate carcinoma cells. On the other hand, Rajasekaran
et al. reported that GCPII associates to the anaphase-promoting complex (APC)
and downregulates its activity, leading to aneuploidy, which suggests an etiologic
role in prostate cancer progression.
59
Colombatti et al. provided another piece of
evidence for the direct involvement of GCPII in oncogenesis. Cross-linking of
GCPII on the plasma membrane by specific antibodies activates a signaling
pathway that leads to NFkB activation and increased expression of IL-6 and
CCL-5, which promote the proliferation of prostate cells.
60
Liu et al. showed that GCPII undergoes internalization via clathrin-coated
pits.
61
The internalization is regulated by binding of the cytoplasmic tail of
GCPII to filamin A, which directs the complex to the recycling endosomal
compartment.
62
Conway et al. show that angiogenesis is impaired in GCPII
-/-
animals and suggest that GCPII promotes epithelial cell invasion via its ability
to facilitate integrin signaling and p21 activated kinase (PAK) activation.
55
Taken together, the internalization of GCPII upon ligand binding, the struc-
tural and sequence similarity with transferrin receptor, and the involvement of
GCPII in cell signaling seem to suggest that GCPII could be a receptor for an
unknown extracellular ligand.
3.5 GCPII Homologs
3.5.1 Human Paralogs
GCPII has several paralogs in humans that are summarized in Table 3.3.
Evolutionarily, the youngest relative of GCPII is PSMA-like protein (PSMAL),
which is only present in primates and is the only protein of this family that lacks
a transmembrane region. It forms a soluble 46 kDa protein of unknown func-
tion and has 97% sequence identity to GCPII.
63
The second closest relative is
GCPIII (with 67% sequence identity; also known as NAALADase II). GCPIII
has NAAG-hydrolyzing activity. The more distant paralogs NAALADase L
and NAALADase L2 are not known to possess any proteolytic activity, and
their physiological role is unknown. Interestingly, the chromosomal position of
NAALADase L2 gene is associated with Cornelia de Lange syndrome (CdLS),
which is a rare developmental and mental retardation syndrome.
64
Table 3.3 Designation of human GCPII and its paralogs.
GCPII family
members
Amino acid
length
Entrez
Gene
Alternative names
Reference
166
GCPII
PSMA, NAALADase,
FOLH1
750
2346
16,63
PSMAL
442
219595
17
GCPIII
NAALADase II
740
10003
17,167
NAALADase L
I100
740
10004
64
NAALADase L2
795
254827
