Chapter 8 : Integrins on Phagocytes

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This chapter reviews the expression, signaling mechanisms, and functions of integrins on phagocytes, summarizing their central roles in host defense and inflammatory processes. Expression of integrins on the plasma membrane requires interaction of the α- and β-chains in the endoplasmic reticulum; unpaired chains are presumably recognized as unfolded and ultimately degraded. Mutations in the β2 gene that lead to severe reduction in expression of the entire family cause leukocyte adhesion deficiency type I (LAD-I), a severe immunodeficiency. Neutrophils express fewer β1 integrins than β2, and most of the β1 integrins are in secretory granules prior to neutrophil activation. Recent studies showed that overexpression of Rap1, or of one of its effectors, regulator of adhesion and cell polarization enriched in lymphoid tissues (RAPL), leads to increased adhesion through αLβ2. In recent years there has been increasing appreciation that ligation of activated integrins not only leads to cell adhesion and spreading, but also transmits signals into cells, a phenomenon called outside-in signaling, to contrast it with inside-out signaling mediating integrin activation. Integrins can associate with several other proteins within the plane of the plasma membrane, which often results in enhanced integrin-mediated signaling. The chapter finally talks about phagocyte-endothelium interactions, neutrophil migration, and monocyte migration.

Citation: Hazenbos W, Brown E. 2009. Integrins on Phagocytes, p 137-152. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch8

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Model for integrin activation. In resting state, integrins do not efficiently bind their ligand; activation by inside-out signaling induces a conformational change that dramatically enhances integrin-ligand interactions. (A) Resting, low-affinity state. Structural analyses revealed that the low-affinity state of resting integrins correlates with a “bent” confirmation. The ligand binding site is unavailable for ligand recognition. In this state, integrins likely exist as monomers diffusely distributed on the plasma membrane. (B) Activated, enhanced affinity state. Cell activation induces inside-out signaling, leading to separation of the integrin α- and β-chain cytoplasmic tails. This separation results in an intramolecular conformational change propagated through the plasma membrane, resulting in unbending of the extracellular domains. The ligand binding site becomes exposed and undergoes additional conformational change, enhancing affinity. This conformational change is thought to occur for both I domain-containing and I domain-lacking integrins; for simplicity, only an I domain-containing molecule is shown. (C) Activated, enhanced avidity state. Inside-out signaling can also lead to clustering of multiple integrin molecules, resulting in enhanced avidity for a multivalent ligand. It has been proposed, at least for αIIbβ3, that this clustering involves oligomerization of β-chain transmembrane domains ( ).

Citation: Hazenbos W, Brown E. 2009. Integrins on Phagocytes, p 137-152. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch8
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Integrins on phagocytes

Citation: Hazenbos W, Brown E. 2009. Integrins on Phagocytes, p 137-152. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch8

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