Biomedical Engineering Reference
In-Depth Information
1.3.1 Homology and Gene Structure
A high degree of homology exists within the DP4-like gene family with all
members sharing 25-60% amino acid sequence identity and 47-77% amino
acid sequence similarity.
7
Notably, FAP and DP4, located adjacent to each
other on the long arm of chromosome 2 (2q24.2 and 2q24.3 respectively), share
52% amino acid identity. The two non-enzyme members, DP6 and DP10,
located on chromosomes 7q36.2 and 2q14.1 respectively, share 53% amino acid
sequence identity, and the most recently identified enzyme members, DP8 and
DP9, located respectively on chromosomes 15q22.32 and 19q13.3, share 61%
amino acid sequence identity. The close proximity and high level of similarity
between the DP4 and FAP genes suggest that they have arisen from a recent
gene duplication event.
7
Likewise, it is possible that DP10, also located on the
long arm of chromosome 2, was derived from either DP4 or FAP, followed by
the divergence of DP6 on chromosome 7. Similarly, the high sequence identity
and shared cytosolic localization suggest that DP8 and DP9 have arisen from a
gene duplication event.
7
Although of varying gene length, the DP4 (82 kb),
FAP (73 kb), DP6 (935 kb), and DP10 genes (1402 kb) all contain 26 exons,
7
further supporting the likelihood of a common gene ancestor. In contrast, the
DP8 (72 kb) gene contains 20 exons,
6
and the DP9 gene contains 19 or 22 exons
dependent on whether the gene is expressed in its short (863-amino-acid) or
long (971 amino acid) forms.
34
Like DP9, short and long transcript variants
with variable length N-termini arising from alternate first exon use exist for
DP6
47,48
, DP10,
49,50
and DP8.
6,51
Differing patterns of expression and tissue
specificity are often associated with these alternative transcripts, but a com-
prehensive study investigating their significance to human biology is yet to be
carried out.
1.4 Protease Members of the DP4-Like Gene Family
1.4.1 DP4 and FAP: Extracellular Proteins
DP4 is the best-characterized member of the DP enzyme family, followed to a
lesser extent by FAP, which was identified almost 20 years after DP4. Both
enzymes are implicated in a number of roles, including tissue remodeling/
wound healing, inflammatory bowel disease, arthritis, type II diabetes, obesity,
and cancer (reviewed in several previous studies
52-55
). In cancer, both DP4 and
FAP play conflicting roles acting as either a tumour suppressor or tumour
promoter depending on the cancer type.
56
DP4 plays a key role in glucose
homeostasis, regulating the activities of GLP-1 and glucose-dependent insuli-
notropic peptide (GIP) via its proteolytic activity, and has thus become a
clinically validated target in the management of type II diabetes (reviewed in
several previous studies
57-59
). FAP is also of clinical relevance, particularly
within a cancer and liver disease setting as discussed below. Here, the expres-
sion patterns and biological importance of DP4 and FAP will be introduced.
