Chapter 18 - Intracellular signaling and perception of neuronal scaffold through integrins and their adapter proteins

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Abstract

Integrin receptors are required for cell adhesion, migration, survival, and proliferation of cells when in contact with the extracellular matrix. In addition, integrins are required for the outgrowth of neurites and formation of glial scaffold in the brain and also for the remodeling and long-term potentiation within synapses. While some of these neuronal functions are expected from studies in nonneuronal cells, such as fibroblasts, other functions, especially at synapses, cannot be studied elsewhere. In this chapter, we will concentrate on the mechanisms that control integrin-mediated signaling and how it is initiated downstream of integrin–ligand interaction. While we address some newer findings concerning the recruitment of paxillin to the integrin–talin–kindlin complex, we will also highlight the central function of paxillin in integrin signaling and how it can interface with other signaling systems controlling neuronal or synaptic functions.

Introduction

With the development of multicellular organisms, cells developed the capacity to recognize and bind to each other using cell–cell adhesion receptors. However, in order to polarize and to maintain a complex tissue organization, cells required receptors of the integrin family to bind and to organize in response to a secreted extracellular scaffold, also called extracellular matrix (ECM). With increasing numbers of different cell types and complexity of organs, new classes of cell–cell interaction systems evolved to control physical interactions and communication among different cell types. On the other hand, in addition to basement membranes and fibrillar protein networks, the pericellular ECM gained new functional capacities to form viscoelastic 3D networks, enabling the formation of a pressurized blood system and internal skeletons of vertebrates (Engler et al., 2009).

Integrin receptors ensure that cells are able to maintain physical contact with their extracellular scaffold in order to keep their spatial organization and connectivity with other cells. One particular hallmark of integrin-dependent adhesion receptors is the ability to mechanically couple their cytoskeleton in form of contractile (stress fibers) or protrusive (filopodia) elements to the ECM while simultaneously perceiving signals regarding the physical properties of the contacted extracellular scaffold (Boettiger, 2012, Friedland et al., 2009). In fact, integrin-mediated cell–matrix adhesions appear to require a constant tugging or pulling, in order to maintain their integrity and physical connection, as well as producing intracellular signals. Whether this need for mechanical stimulation is also experienced by integrins located on dynamic projections of neurons such as dendritic spines (Fischer et al., 1998) needs to be shown. Although the nominal value of tensional forces and stiffness of the extracellular scaffold in the central nervous system is much lower compared to the muscle or bone, similar mechanisms appear to regulate integrin-dependent cell–matrix adhesions and signaling thereof (Bernard-Trifilo et al., 2005, Engler et al., 2006, Kramar et al., 2006). In addition, it is apparent that classical integrin-dependent functions, such as adhesion, migration, and proliferation, are also maintained in the central nervous system (Blaess et al., 2004, Graus-Porta et al., 2001, Myers et al., 2011). In addition, integrin downstream effectors such as integrin-linked kinase (ILK; Mills et al., 2006, Niewmierzycka et al., 2005) or focal adhesion kinase (FAK; Liu et al., 2004, Moeller et al., 2006, Rico et al., 2004, Shi et al., 2009) perform critical functions in the central nervous system, either directly in response to integrins or within signaling pathways known to synergize or cross talk with integrins. While integrin function is critically required for organization of the tissue scaffold and lamination of the brain cortex (Graus-Porta et al., 2001), it is dispensable for neuronal binding to and migration along the radial glia. However, in the absence of α3-, α5-, or α6-integrin, migration along the radial glia is not correctly initiated or terminated, leading to the perturbation of the lamination of the cortex (Georges-Labouesse et al., 1998, Marchetti et al., 2010, Marchetti et al., 2013, Schmid et al., 2004). More surprisingly, perturbations of long-term potentiation (LTP) are observed after conditional deletion of β1 in forebrain excitatory neurons in adult animals (Huang et al., 2006), especially considering that dendritic and synaptic differentiations are not affected by β1-integrin deletion. Because synaptic function and LTP are not easily related with integrin-dependent adhesive or migratory behaviors in nonneuronal cells, the analysis of integrin function in this specific situation is particularly challenging and a clear role for integrins has not been established (see below).

Although not yet specifically determined in neurons or glial cells, we expect nevertheless that due to the paramount importance of integrin function for cells and organs, fundamental aspects of integrin adhesion and signaling are preserved. Here, we will summarize recent developments in integrin signaling obtained from studies in fibroblasts, in order to compare it with brain or synaptic functions, when available. Importantly, we would also like to discuss cross talks of integrin signaling pathways with other receptor systems, in order to provide ideas how integrin-mediated signaling can influence neuronal and glial behavior.

Section snippets

Integrin Structure Function Relationship

Integrins are heterodimeric transmembrane receptors consisting of a noncovalently associated α- and β-subunit. Twenty-four different heterodimers have been identified formed from 18 different α-subunits and 8 β-subunits (Hynes, 2002). Unless the α-subunit exhibits an I-domain (I for inserted), specificity for extracellular ligands is determined by both subunits. While the β-subunit provides a metal ion-dependent interaction with an acidic amino acid of the ligand (e.g., Asp (D) in fibronectin

Mechanosignaling in Integrin-Dependent Cell–Matrix Adhesions

Evidence of cell–matrix adhesion-mediated intracellular signaling was suggested after cloning and subcellular localization of a major target of the Rous sarcoma virus-encoded oncoprotein pp60v-src (Schaller et al., 1992). The localization of this “focal adhesion” kinase together with other major v-src targets, such as paxillin, led to the concept that cell–matrix adhesions are critical sites of intracellular signaling (Burridge et al., 1992, Turner et al., 1990). Mapping of the respective focal

Mechanism of Paxillin Recruitment to Cell–Matrix Adhesions

Parallel to the biochemical and cell-biological characterization of integrin-dependent signaling, researchers analyzed the mechanisms that allowed cells to respond to mechanical or physical changes in their environment. For example, it was noted that cell survival was critically dependent on the shape and geometry of the presented ECM (Chen et al., 1997). In another example, integrin-dependent adhesion to beads was reinforced when force was applied to the beads (Choquet et al., 1997).

Paxillin, at the Origin of an Integrin-Mediated Signaling Hub

Paxillin is recruited to integrin-dependent cell–matrix adhesions by its C-terminal LIM domains, while the N-terminal domain is primarily nonstructured containing 3–5 (depending on the isoform) short Leu-Asp-rich helical domains (LD repeats), interspersed with several serine and tyrosine phosphorylation sites (Alam et al., 2014, Brown et al., 1996, Tumbarello et al., 2002). The LIM domains also bind to PTP-PEST, a tyrosine phosphatase, which is essential for development and negatively regulates

Integrin Signaling and LTP at the Synapse

Several integrin isoforms have been identified to localize to the pre- or postsynaptic side. In addition, the deletion of the β1- or α-subunit has caused a loss of LTP. On the other hand, the activation of LTP and an enlargement of dendritic spines have been observed by the addition of MMP-9 (Wang et al., 2008), a key protease involved in the degradation of ECM and the production of integrin-binding soluble ECM fragments, also termed matricryptins (Ricard-Blum and Salza, 2014). One striking

Conclusion

Although integrin-dependent adhesion signaling and its important role in neurite growth and synaptic function have been known for several years, new mechanistic insights have been recently made. This progress also shows that more detailed information is required to understand how mechanically mediated processes translate into integrin-mediated signaling at the level of the ECM–F-actin connection. Joining forces and analysis from different fields will eventually be required to unravel the

Acknowledgments

The authors thank Ellen Van Obberghen-Schilling for suggestions and critical reading of the manuscript. This work was initiated and supported by COST Action BM1001.

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