Integrin activation—the importance of a positive feedback

Abstract

1Integrins mediate cell adhesion and are essential receptors for the development and functioning of multicellular organisms. Integrin activation is known to require both ligand and talin binding and to correlate with cluster formation but the activation mechanism and precise roles of these processes are not yet resolved. Here mathematical modeling, with known experimental parameters, is used to show that the binding of a stabilizing factor, such as talin, is alone insufficient to enable ligand-dependent integrin activation for all observed conditions; an additional positive feedback is required.Keywords Talin, integrin, receptor activation, Master equation, positive feedback 2 IntroductionIntegrins, large membrane-spanning heterodimeric proteins, were so named for their ability to link the extracellular and intracellular skeletons [Tamkun et al., 1986]. As an important class of cell adhesion receptors they participate in a wide-range of biological interactions, including development, tissue repair, angiogenesis, inflammation and hemostasis [Horwitz & Webb, 2003]. Cell adhesion and detachment as well as controlled actin polymerisation inside the cell are of particular importance in cell migration. The speed of cell movement depends on the density of integrins and ligands as well as their affinity of binding [Palecek et al., 1997]. Integrins are key components of focal adhesions, dynamic multi-protein complexes that are involved in the regulation of cell adhesion and migration. Focal adhesions [Zamir & Geiger, 2001] provide a physical link between integrins and the actin cytoskeleton as well as sites for signal transduction into the cell interior. Information about identified interactions and players in these complexes is ever-increasing but our overall understanding of how the ensemble works remains relatively poor.According to the current model of integrin activation, ligand binding shifts the equilibrium between different integrin conformations to the active one [Hynes, 2002]. The two extreme conformations of this allosteric protein are a bent or 'closed' conformation which represents the low affinity state for ligand and an 'open' conformation that will bind with high affinity to ligand. Conformational changes in the extracellular domain affect the cytoplasmic tails, which are separated in the open conformation but not in the closed. Separation of the cytoplasmic domains promotes their interaction with cytoskeletal and signal transduction molecules, and thus the activation of integrins and downstream signaling. The conformational equilibrium can be influenced both by ligand binding to the extracellular domain (outside-in signaling) and by binding of cytoplasmic proteins to the separated cytoplasmic domains (inside-out signaling). As well as changes in affinity induced by structural changes, integrins can also modulate their avidity by clustering, thus changing the valency of their interactions with ligand [Carman & Springer, 2003].Previous theoretical studies have addressed the mechanism of integrin clustering...

Integrin activation

“…On the basis of studies using crystallography, NMR, electron microscopy and FRET (Förster resonance energy transfer), integrins appear to assume multiple conformations [2,[11][12][13]. Several studies suggest that the bent conformation is a low-affinity state, whereas the extended conformation is associated with a high-affinity state of integrins [12][13][14][15][16][17][18].…”

Platelet integrin αIIbβ3: activation mechanisms

“…Although talin is clearly implicated in the activation process, several lines of evidence indicate critical roles for other binding partners, both working cooperatively with talin‐H as co‐regulators and as suppressors of integrin activation. Observations supporting a mechanism more complex than mediated by talin‐H alone are: (i) the C‐terminus of β 3 CT, far beyond the talin‐H binding sites, is critical for inside‐out as well as outside‐in signaling [92]; (ii) some point mutations, such as S 752 P in the β 3 CT, which have no effect on talin‐H binding and its unclasping function, still dramatically impair integrin activation [39]; (iii) over‐expression of talin‐H does not achieve full activation of α IIb β 3 , relative to that induced by deletion of either the α llb or β 3 CT [39]; (iv) mathematical modeling predicts that talin alone is insufficient to enable ligand‐dependent integrin activation [93]and (v) intuitively, other CT binding partners, which may not possess the molecular features needed to initiate unclasping, may still bind and/or displace talin. One such potential co‐regulator may be β 3 ‐endonexin, a 111 amino acid protein present in platelets, which binds to the C‐terminal NITY 759 motif [94].…”

Integrin activation in the immune system

“…This is a rather challenging task, as it needs accurate quantitative experimental data, which currently are largely unavailable. However, approaches in this direction have started to emerge 61–63. Combining topological and dynamic network analysis may lead to computer simulation of the integrin activation process in leukocytes thus allowing in silico experimentations that are useful to accelerate pharmacological research in inflammation and immune diseases.…”