Chapter 18 - Intracellular signaling and perception of neuronal scaffold through integrins and their adapter proteins
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.
References (113)
- et al.
Transmembrane signal transduction by integrin cytoplasmic domains expressed in single-subunit chimeras
J. Biol. Chem.
(1994) - et al.
Integrin alpha3beta1 (CD 49c/29) is a cellular receptor for Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) entry into the target cells
Cell
(2002) Mechanical control of integrin-mediated adhesion and signaling
Curr. Opin. Cell Biol.
(2012)- et al.
Cell adhesion: a FERM grasp of the tail sorts out integrins
Curr. Biol.
(2012) Integrin alphaIIbbeta3 activation in Chinese hamster ovary cells and platelets increases clustering rather than affinity
J. Biol. Chem.
(2010)- et al.
The Talin head domain binds to integrin beta subunit cytoplasmic tails and regulates integrin activation
J. Biol. Chem.
(1999) - et al.
Rab25 associates with alpha5beta1 integrin to promote invasive migration in 3D microenvironments
Dev. Cell
(2007) - et al.
Focal adhesion disassembly requires clathrin-dependent endocytosis of integrins
FEBS Lett.
(2009) - et al.
“Inside-out” signal transduction inhibited by isolated integrin cytoplasmic domains
J. Biol. Chem.
(1994) - et al.
Cross-correlated fluctuation analysis reveals phosphorylation-regulated paxillin-FAK complexes in nascent adhesions
Biophys. J.
(2011)
Extracellular matrix rigidity causes strengthening of integrin-cytoskeleton linkages
Cell
Function of liprins in cell motility
Exp. Cell Res.
Intact alphaIIbbeta3 integrin is extended after activation as measured by solution X-ray scattering and electron microscopy
J. Biol. Chem.
Matrix elasticity directs stem cell lineage specification
Cell
Rapid actin-based plasticity in dendritic spines
Neuron
Beta1-class integrins regulate the development of laminae and folia in the cerebral and cerebellar cortex
Neuron
Lamellipodia nucleation by filopodia depends on integrin occupancy and downstream Rac1 signaling
Exp. Cell Res.
Integrins: bidirectional, allosteric signaling machines
Cell
An integrin binding peptide reduces rat CA1 hippocampal long-term potentiation during the first few minutes following theta burst stimulation
Neurosci. Lett.
Cell movement is guided by the rigidity of the substrate
Biophys. J.
Ubiquitination of alpha 5 beta 1 integrin controls fibroblast migration through lysosomal degradation of fibronectin-integrin complexes
Dev. Cell
Mechanisms of integrin activation and trafficking
Curr. Opin. Cell Biol.
Distinct roles of talin and kindlin in regulating integrin alpha5beta1 function and trafficking
Curr. Biol.
EphB receptors regulate dendritic spine morphogenesis through the recruitment/phosphorylation of focal adhesion kinase and RhoA activation
J. Biol. Chem.
Essential function of PTP-PEST during mouse embryonic vascularization, mesenchyme formation, neurogenesis and early liver development
Mech. Dev.
Target-derived matricryptins organize cerebellar synapse formation through alpha3beta1 integrins
Cell Rep.
The paxillin LD motifs
FEBS Lett.
How to find a leucine in a haystack? Structure, ligand recognition and regulation of leucine-aspartic acid (LD) motifs
Biochem. J.
PAK3 mutation in nonsyndromic X-linked mental retardation
Nat. Genet.
Protein tyrosine phosphatase-PEST regulates focal adhesion disassembly, migration, and cytokinesis in fibroblasts
J. Cell Biol.
Induction of cell polarization and migration by a gradient of nanoscale variations in adhesive ligand spacing
Nano Lett.
Integrin dynamics produce a delayed stage of long-term potentiation and memory consolidation
J. Neurosci.
Force and focal adhesion assembly: a close relationship studied using elastic micropatterned substrates
Nat. Cell Biol.
Integrin signaling cascades are operational in adult hippocampal synapses and modulate NMDA receptor physiology
J. Neurochem.
The integrin beta tail is required and sufficient to regulate adhesion signaling to Rac1
J. Cell Sci.
Beta1-integrins are critical for cerebellar granule cell precursor proliferation
J. Neurosci.
Sorting nexin 17 prevents lysosomal degradation of beta1 integrins by binding to the beta1-integrin tail
Nat. Cell Biol.
Identification of LIM3 as the principal determinant of paxillin focal adhesion localization and characterization of a novel motif on paxillin directing vinculin and focal adhesion kinase binding
J. Cell Biol.
Src and FAK kinases cooperate to phosphorylate paxillin kinase linker, stimulate its focal adhesion localization, and regulate cell spreading and protrusiveness
Mol. Biol. Cell
Tyrosine phosphorylation of paxillin and pp125FAK accompanies cell adhesion to extracellular matrix: a role in cytoskeletal assembly
J. Cell Biol.
Talins and kindlins: partners in integrin-mediated adhesion
Nat. Rev. Mol. Cell Biol.
Type I phosphatidylinositol phosphate kinase beta regulates focal adhesion disassembly by promoting beta1 integrin endocytosis
Mol. Cell. Biol.
Geometric control of cell life and death
Science
The mechanisms and dynamics of αvβ3 integrin clustering in living cells
J. Cell Biol.
Paxillin comes of age
J. Cell Sci.
Distinct roles for paxillin and Hic-5 in regulating breast cancer cell morphology, invasion, and metastasis
Mol. Biol. Cell
Stretching single talin rod molecules activates vinculin binding
Science
Multiscale modeling of form and function
Science
Clathrin mediates integrin endocytosis for focal adhesion disassembly in migrating cells
J. Cell Biol.
Mechanically activated integrin switch controls alpha5beta1 function
Science
Cited by (10)
Attenuation of the extracellular matrix increases the number of synapses but suppresses synaptic plasticity through upregulation of SK channels
2021, Cell CalciumCitation Excerpt :During prenatal and early postnatal brain development, the ECM provides either adhesive or repellent cues that control cell migration and navigation of growing axons. These processes involve signaling through a diverse group of transmembrane receptors, such as integrins [3], ApoER2, VLDL, EphB [4,5], and RPTPσ [6,7]. In the mature brain, a number of ECM molecules and ECM receptors trigger various biochemical cascades that regulate neuronal function [8].
Signals from the Fourth Dimension Regulate Drug Relapse
2016, Trends in NeurosciencesCitation Excerpt :For example, cocaine increases polysialylated neural CAM (NCAM) in the PFC [101], and Nrcam knockout mice show reduced rewarding effects by alcohol, morphine, cocaine and amphetamine [102,103]. Integrins are perhaps the best-characterized CAMs in terms of synaptic plasticity [104]. Extinction from cocaine self-administration is associated with an increase in the β3-integrin subunit in the NAcore [105], and treatment with the RGD peptide antagonist that prevents the binding of integrins to the ECM attenuates the increase in β3-integrin as well as the constitutive reduction in surface expression of GluR2 seen after withdrawal from cocaine [85,106].
Preface
2014, Progress in Brain ResearchPaxillin: A Hub for Mechano-Transduction from the β3 Integrin-Talin-Kindlin Axis
2022, Frontiers in Cell and Developmental Biology