Biomedical Engineering Reference
In-Depth Information
M-positive mononuclear cells in
bone marrow and in circulation. Stimulation through
Multinuclear osteoclasts are derived from
α
α
V
β
3
-integrin is suggested
to be essential for osteoclast dif erentiation.
β
3
-integrin binds several ECM
proteins including virtonectin, osteopontin, and bone sialopontin. RGD-
containing peptides and blocking antibodies to
α
V
β
3
were shown to inhibit bone
resorption
in vivo
and
in vitro
suggesting its important role in regulating osteoclast
development and function.
α
V
INTRACELLULAR SIGNALING
Integrins dif er from other receptors by being able to conduct signals not only
from extracellular stimuli to induce intracellular changes (outside-in signaling)
but also from intracellular stimuli to cause extracellular changes (inside-out
kinase activity of their own. Signals from integrins inside the cell are dependent on
binding to accessory molecules that contribute further to activation of intracellular
pathways. At present more than 150 signaling, structural and adaptor molecules
for integrins are identii ed. h e interaction of
β
2
-integrins with their ligands
(ICAM-1) results in complex formation and phosphorylation transducing signals
through Grb2, SOS and Shc tyrosine kinases followed by MAPK activation. h e
outside-in signaling through
β
3
-integrins is mediated by integrin-linked
kinases (ILK). ILK is a multifunctional protein binding a number of adaptor
proteins that participate in cytoskeletal dynamics and cell signaling and assembling
them into functional complexes. Binding of
β
1
- and
-integrins to ILK stimulates kinase
activity of ILK controlling phosphorylation of Akt at Ser473 in a PI3-kinase
dependent manner. ILK activity may be also upregulated by hypoxia and several
growth factors as insulin and PGDF and downregulated by a specii c phosphatase
(Dedhar 1999). Full functional ILKs have been shown to be essential for leukocyte
adhesion, migration and proliferation. Talin is a component of the leading edge of
activated lymphocytes and of the immunological synapse. Talin binding is believed
to be the common i nal step in integrin activation. Talin binds to cytoplasmic
tails of
β
subunits. Activated
integrins, talin, vinculin and actin i laments form a link between the cytoskeleton
and ECM. Less is known about signal transduction net of
β
-integrins, disrupting interface between the
α
and
β
α
4
-
integrin is directly associated with adaptor molecule paxillin. Paxillin binding to
α
α
-integrins. h e
-integrin tail has inhibitory ef ects blocking Rac. Dissociation of
α
4
-integrin/
paxillin complex removes Rac suppression (Rose 2007).
For regulation of cell migration, survival, proliferation and tissue-specii c
gene expression, integrins cooperate with several groups of receptors (Huveneers
2007): chemotactic receptors (G-protein coupled receptors, GPCR), growth factor
receptors (receptor tyrosine kinase), immunoreceptors (FcRs and T cell receptor),
and, recently, pathogen-sensitive TLRs.
