Biomedical Engineering Reference
In-Depth Information
1.6 DP Substrates: Biological Relevance to Human
Health and Disease
Discovered over 40 years ago, a number of diverse biological substrates for
DP4 have been identified. In contrast, only a limited number of potential FAP
substrates have been found. Based on the high degree of sequence identity and
structural similarity of DP8 and DP9 with DP4, it is thought that substrate
preferences would be the same and potential substrates shared; however, the
intracellular vs. extracellular localization makes this unlikely. Recently, DP8/9
cleavage of known DP4 substrates has been demonstrated in vitro, and a bio-
logical substrate of DP9 identified. In our own studies, we have identified two
potential natural substrates of DP8/9 that may prove to be of interest in future,
although they are not discussed here. DP4 is known to cleave numerous bio-
logically active peptides, hormones, and chemokines sourced from a diverse
range of families including: the pancreatic polypeptide family (NPY, PYY),
pituitary adenylate cyclase-activating peptide (PACAP)/Glucagon family
(GLP-1, glucagon, GLP-2, GIP, growth-hormone-releasing factor (GRF),
vasoactive intestinal peptide (VIP), PACAP27/38, peptide histidine methionine
(PHM)), chemokines (Mig, interferon-g inducible protein (IP-10), interferon
inducible T cell a-chemoattractant (I-TAC), stromal derived factor (SDF)1-a/
b, human analog of macrophage inflammatory protein-1a (LD78b), RANTES
(regulated on activation, normal T cell expressed and secreted), eotaxin, mac-
rophage-derived chemokine (MDC)), and other molecules such as the neuro-
peptides; substance P, b-casomorphin, endomorphin, and morphiceptin (Table
1.1). Proteolytic cleavage by DP4 can lead to the inactivation, activation, or
alteration in receptor specificity of a substrate, thus leading to changes in sig-
naling pathways and numerous biological processes. Many DP4 substrates
exert their effects on a number of physiological processes, but in the context of
this review only the main ones will be discussed.
1.6.1 Glucose Homeostasis and Nutritient Metabolism
To date, in vivo cleavage has been demonstrated only for a few of the potential
DP4 substrates with the most notable of these including GLP-1 and GIP. GLP-
1 and GIP are highly insulinotrophic proteins, functioning as potent stimula-
tors of glucose-dependent insulin secretion. In addition, GLP-1 contributes to
blood-glucose homeostasis by inhibiting the secretion of glucagon, gastric
emptying and reducing food intake. Following the intake of food, the levels of
GLP-1 will rise rapidly in response to the increasing blood glucose levels. Here
DP4 plays an important role in maintaining glucose homeostasis by rapidly
degrading the N-termini of GLP-1
(7-36)
and GIP
(1-42)
converting them into
biologically inactive forms GIP
(3-42)
and GLP-1
(9-36)
.
147-149
Inhibition or loss
of DP4 activity results in increased levels of stable GLP-1
(7-36)
, leading to
improved glucose tolerance via increases in the glucose-stimulated insulin
secretion and decreased glucagon secretion (reviewed in several previous
studies
58,59,150,151
). DP4 plays an important role in regulating the activity of
