Biomedical Engineering Reference
In-Depth Information
Bershadsky. et. al.. 2006).. Ligand. binding. in. itself. alters. integrin. conformation. and. afin-
ity,. and,. in. the. case. of. multivalent. ligands,. integrin. clustering.. With. increased. integrin.
recruitment,.these.early.cell-matrix.contacts.form.anchoring.focal.complexes.at.the.lamel-
lipodium. leading. edge. that. are. reinforced. intracellularly. to. form. macromolecular. focal.
adhesion.assemblies.upon.increased.intra-.and/or.extracellular.tension.(Figure.20.1c).
The. regulation. of. focal. adhesion. formation. in. adherent. cells. is. highly. complex. and.
involves.both.the.turnover.of.single.integrins.and.the.reinforcement.of.the.focal.adhesion.
plaque. by. protein. recruitment.. It. follows. that. focal. adhesions. provide. structural. integ-
rity.and.dynamically.link.the.ECM.to.intracellular.actin.ilaments.(Figure.20.2),.directly.
facilitating.cell.migration.and.spreading.through.continuous.regulation.and.turnover.of.
a.diverse.network.of.proteins..Furthermore,.in.combination.with.growth.factor.receptors,.
these. macromolecular. assemblies. initiate. complex. signaling. pathways. and. regulate. the.
activity.of.nuclear.transcription.factors—processes.crucial.to.cell.growth,.differentiation,.
and.survival,.as.will.be.discussed.
Ward.and.Hammer.developed.a.model.of.adhesion.strengthening.(Ward.and.Hammer.
1993),. which. predicts. large. increases. in. adhesion. strength. following. increased. receptor.
clustering.and.adhesion.size,.marked.by.an.elongation.of.the.adhesion.plaque..This.pro-
cess.is.believed.to.be.due.to.an.increase.in.tension.at.the.adhesion.site,.and.focal.adhesion.
reinforcement.has.been.shown.to.be.proportional.to.intracellular.tension.(Balaban.et.al..
2001),.indicating.that.adhesion.sites.act.as.dynamic.mechanosensors.(Schwarz.et.al..2006).
that.form.additional.contact.points.with.the.underlying.substratum.in.response.to.internal.
force. generation.. Preceding. this. focal. adhesion. reinforcement,. a. tightly. regulated. series.
of.temporospatial.events.occurs,.mediating.integrin.clustering.in.an.anisotropic.manner.
in.the.direction.of.force.(Besser.and.Safran.2006)..This.integrin.clustering.has.a.discrete.
lateral. spacing,. which. lies. in. the. realm. of. 70-80.nm. (deBeer. et. al.. 2010),. and,. as. will. be.
discussed,. is. a. key. indicator. of. the. mechanisms. involved. in. the. nanofeature-mediated.
perturbation.of.focal.adhesion.formation.
Alpha-actinin
F-actin
Src
Vinculin
Paxillin
Talin
FAK
Beta
Plasma membrane
Integrin
Fibronectin
Alpha
Substrate
Figure 20.2
(See companion CD for color igure.)
.Simpliied.overview.of.the.focal.adhesion..Focal.adhesions.are.macro-
molecular. structures. that. serve. as. mechanical. linkages. of. the. cell. cytoskeleton. (F-actin). to. the. ECM. and. as.
biochemical. signaling. hubs. involved. with. the. transmission. of. external. mechanical. forces. through. multiple.
signaling.proteins.that.interact.at.sites.of.integrin.binding.and.clustering.
