Biomedical Engineering Reference
In-Depth Information
Some integrin-ligand pairings are more common than others, and specific
sequences that appear frequently have been identified. Among the most common
of these is the arginine-glycine-aspartic acid (RGD) sequence. Approximately one-
third of integrins have binding sites for the RGD tripeptide, which can be found on
many ECM proteins, including fibronectin, vitronectin, fibrinogen, and the latency-
associated peptide (LAP) complex part of inactive transforming growth factor
.
Although the RGD sequence is not readily exposed by collagen or laminin, there are
cases in which denaturation or cleavage of these proteins results in exposure of the
RGD sequence and subsequent integrin binding.
11
The RGD-binding integrins
include all five of the
b
3 integrin.
RGD binding integrins can bind a large number of ECM and soluble vascular ligands.
The ligands that contain the specific tripeptide active site bind with the integrins
through an identical atomic basis.
12
The affinity of integrins to the RGD sequence has been exploited extensively in
tissue engineering research and therapy development. Recently, nanocarriers with
RGD tethering on the surface have been shown to use the integrin-ligand specificity
to target tumors that are rich with RGD-binding integrins.
13
Optimization of this
drug delivery vehicle to increase the specificity, targeting, and loading efficiency of
the nanocarrier can have a significant therapeutic impact. RGD peptides have also
been shown to positively influence the differentiation of mesenchymal stem cells into
articular chondrocytes
14
as well as the development of functional cardiac tissue from
neonatal cardiac cells.
15
Similar to the RGD sequence, the tripeptide leucine-aspartic acid-valine (LDV) is
a common ligand among a group of integrins. LDV is an acidic motif that is
functionally related to RGD and is suggested to bind to integrin receptors in a similar
fashion.
16
LDV is present on fibronectin, and a related sequence is present on
vascular cell adhesion molecule 1 (VCAM-1). The
a
V integrins, two
b
1 integrins, and the
a
IIb
b
b
a
b
2 integrins as well as
4
1,
7
9,11,16
contain a binding site for the LDV ligand.
Although RGD-binding integrins can recognize the RGD sequences that are
exposed when collagen is degraded or cleaved, another specific amino acid sequence
can be recognized by integrins when collagen structure is intact. The glycine-
phenylalanine-hydroxyproline-glycine-glutamic acid-arginine (GFOGER) sequence
exists on triple helical collagens. The sequence is recognized by a group of collagen-
binding integrins,
a
b
a
b
9
1, and
4
1, an important integrin in hemostasis. It is
speculated that the GFOGER sequence is exposed once per microfibril unit of
collagen.
11
The proximity of the ligand sequences on a microfibril of collagen
promotes integrin clustering and focal adhesion formation, the importance of which
has already been discussed.
Similar to collagen, binding sequences on laminin are only recognized by RGD-
binding integrins if the ECM protein has been disrupted. The integrin binding
sequence tyrosine-isoleucine-glycine-serine-arginine (YIGSR) has been discovered
as the minimum sequence necessary to promote binding and adhesion between
integrin receptors and epithelial cells on intact laminin.
17
YIGSR is found to be
highly active in epithelial cells yet much less active in chondrocytes, osteoblasts, and
fibroblasts.
including
a
2
b
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