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Integrin activation in the immune system

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Abstract Modulation of leukocyte adhesiveness is critical to leukocyte function during the immune response. A central paradigm in this phenomenon is represented by integrin activation, which is controlled by inside‐out signal transduction mechanisms triggered by selectins, chemoattractants and TcR‐bound Ag and facilitated by mechanochemical forces. Integrins are heterodimeric adhesive receptors differently expressed on all leukocyte subtypes. At least two distinct modalities of integrin activation are known, namely conformational changes, leading to increased affinity, and lateral mobility leading to increased valency, both enhancing cell avidity (adhesiveness). Several signal transduction events have been correlated to integrin activation in leukocytes. The complexity of intracellular signaling networks leading to leukocyte integrin activation is likely functional to generate robustness and fine tuning of integrin activation allowing integration of qualitative and quantitative variations of extracellular signals leading to leukocyte‐, agonist‐ and integrin‐specific control of adhesion. In this context, the recent modular abstraction proposed for the functional architecture of biological networks may provide a powerful paradigm to understand regulation and specificity of signaling events. Accordingly, pro‐adhesive intracellular signaling networks may be organized in regulatory signalosomes, or modules, corresponding to discrete clusters of interacting signaling proteins, with some devoted to context‐dependent regulation of specificity and dynamics of integrin activation. The principles and technologies of systems biology, and more specifically of network theory, may help to address this complexity and unveil the inner logic governing leukocyte recruitment during the immune response. Copyright © 2009 John Wiley & Sons, Inc. This article is categorized under: Biological Mechanisms > Cell Signaling

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The pro‐adhesive signaling network. The graph shows the 157 direct interactions between the 64 proteins involved in integrin regulation. The graph is intended only to illustrate the complexity of the network even not including the first direct interactors of all nodes. It is evident that few nodes (in yellow, degree > 6) are target of the majority of interactions, suggesting their role as hubs supporting the scale‐free topology of the network [64]. The direction of informational flow is not represented.

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The multistep model of leukocyte recruitment. The diagram represents the sequence of cellular events (bottom) and the molecular mechanisms (top) controlling leukocyte recruitment. Shown are regulatory molecular interactions between Selectins and Mucins, Integrins and Immunoglobulin‐like ligands, chemoattractants and heterotrimeric Gi protein‐coupled receptors (GPCRs,) along with potential signaling networks regulating both leukocyte rolling and arrest. Red arrows indicate the cellular events in which the corresponding molecular mechanisms are involved.

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Modalities of integrin activation. The diagram shows the two main modalities of integrin triggering. Affinity triggering is accompanied by appearance of molecular “activation” epiotpes testifying the increasing binding energy for the ligand and recognized by specific reporter monoclonal antibodies. Lateral mobility on the plasma membrane may lead to increased valency, but also to facilitated ligand engagement and, importantly, to outside‐in signaling events stabilizing cell arrest. Affinity and lateral mobility should be considered concurrent phenomena.

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Integrin affinity triggering. The diagram refers to the LFA‐1 affinity‐triggering model. Shown is the dynamic equilibrium between three conformers displaying low‐, low/intermediate‐ and high affinity for ICAM‐1. The progressive extension of the heterodimer is accompanied by increasing topological availability of the I‐domain and I‐like domain (in yellow), which are involved in ligand binding with increasing affinity.

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