Thy-1/CD90 a Bidirectional and Lateral Signaling Scaffold - PubMed (original) (raw)

Review

Thy-1/CD90 a Bidirectional and Lateral Signaling Scaffold

Lisette Leyton et al. Front Cell Dev Biol. 2019.

Abstract

Thy-1/CD90 is a glycoprotein attached to the outer face of the plasma membrane with various functions, which depend on the context of specific physiological or pathological conditions. Many of these reported functions for Thy-1/CD90 arose from studies by our group, which identified the first ligand/receptor for Thy-1/CD90 as an integrin. This finding initiated studies directed toward unveiling the molecular mechanisms that operate downstream of Thy-1/CD90 activation, and its possible interaction with proteins in the membrane plane to regulate their function. The association of Thy-1/CD90 with a number of cell surface molecules allows the formation of extra/intracellular multiprotein complexes composed of various ligands and receptors, extracellular matrix proteins, intracellular signaling proteins, and the cytoskeleton. The complexes sense changes that occur inside and outside the cells, with Thy-1/CD90 at the core of this extracellular molecular platform. Molecular platforms are scaffold-containing microdomains where key proteins associate to prominently influence cellular processes and behavior. Each component, by itself, is less effective, but when together with various scaffold proteins to form a platform, the components become more specific and efficient to convey the messages. This review article discusses the experimental evidence that supports the role of Thy-1/CD90 as a membrane-associated platform (ThyMAP).

Keywords: GPI-anchor; PLATFORM; Thy-1 (CD90); integrin; membrane-associated; syndecan 4.

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Figures

FIGURE 1

FIGURE 1

Schematic representation of the Thy-1/CD90 protein. The Thy-1/CD90 GPI anchor appears inserted in the outer leaflet of the plasma membrane. The Thy-1/CD90 regions that interact with integrins (RLD) and Syndecan-4 (HBD, heparin-binding domain) are indicated.

FIGURE 2

FIGURE 2

Schematic model for Thy-1-dependent signaling and cytoskeleton regulation induced by αvβ3 integrin-binding. (A) Thy-1/CD90 nanoclusters at the neuronal plasma membrane dynamically associate or disassociate from CBP in lipid microdomains. Phosphorylated CBP serves as a docking site for active Src, which phosphorylates and activates p190RhoGAP that in turn activates the RhoA GTPase that hydrolyses GTP to GDP, inactivating RhoA. (B) Binding of αvβ3 integrin from astrocytes to Thy-1/CD90 induces clustering around CBP-Src-containing domains, recruiting Csk. Csk phosphorylates Src on Y527 and switches off Src activity. Inactive Src moves away from the Thy-1-CBP-Csk complex, inactivating p190RhoGAP. GAP inactivation increases RhoA activity, activating its effector ROCK, thereby leading to increased phosphorylation of cofilin and MLCII, and altering actin cytoskeleton dynamics.

FIGURE 3

FIGURE 3

Thy-1/CD90 binds to αvβ3 integrin and Syndecan-4 and activates Rac1. The astrocyte cell line DI TNC1 was incubated in serum-free medium and then stimulated with Thy-1-Fc-Protein A(RLD)-Sepharose beads (solid line), Thy-1 (RLE) or Thy-1 (AEAAA) (dashed lines) for different periods of time. A pull-down assay for active Rac was performed by affinity-precipitating the cell lysates. Total Rac1 from whole cell lysates and active Rac1 were visualized by immunoblotting with anti-Rac1 polyclonal antibody. Lines are a schematic representation of the results obtained in these experiments (Kong et al., 2013) indicating the fold-increase in Rac1 activity normalized to total protein present in the input lysate (Relative Rac1 activity).

FIGURE 4

FIGURE 4

Thy-1-induced astrocyte adhesion and migration. In astrocytes, Thy-1/CD90 binding to integrin microclusters induces receptor oligomerization and leads to the formation of bigger clusters and integrin activation. Integrin then recruits signaling molecules, such as PLCγ. Active PLCγ hydrolyzes PIP2, generating diacylglycerol (DAG) and IP3. The latter activates the inositol 1,4,5-trisphosphate receptor (IP3R) to allow the release of Ca2+ from intracellular stores such as the endoplasmic reticulum (ER lumen is shown). Increased intracellular Ca2+ concentration opens the hemichannels (Connexin 43 and Pannexin 1), leading to the consequent release of ATP to the extracellular medium. Locally increased ATP concentration activates P2X7 receptors, which allow Ca2+ entry into the cell. This signaling pathway is part of a more complex cascade of reactions leading to cell polarization, adhesion and migration [more details in Alvarez et al. (2016) and Lagos-Cabré et al. (2018)].

FIGURE 5

FIGURE 5

The extracellular Thy-1-linked membrane-associated platform (ThyMAP). Data has been obtained in different cells, as indicated by different textures in the plasma membrane. Thy-1/CD90 binding to integrin occurs in trans (activating) and in cis (regulating). (A) Thy-1/CD90 binding to PMN cells through αMβ2 and α_X_β2 integrins promotes transendothelial migration of these cells, facilitating their arrival to the inflamed tissue. The interaction also induces production of MMP9 and CXCL8. (B) In addition, Thy-1/CD90 crosslinking with antibodies or by binding to αvβ3 integrin in trans forms Thy-1/CD90 nanoclusters and signals to the interior of the cell through the transmembrane adaptor CBP, which transiently confines Thy-1/CD90 by engaging the actin cytoskeleton. (C) Thy-1/CD90 also forms a ternary complex with α5β1 integrin, and possibly with αvβ3, to facilitate melanoma or astrocyte migration, respectively. (D) The regulatory role of Thy-1/CD90 appears to occur in a cis interaction with αvβ3 integrin. This cis interaction decreases integrin avidity for ECM proteins and could regulate Thy-1/CD90 tumor suppressor or tumor promoter activity and, additionally, control the interaction of integrins with CD97. (E) The latter could also interact directly with Thy-1/CD90. Polymorphonuclear cells (PMNC); Endothelal cells (EC); Transendothelial migration (TEM).

References

    1. Alvarez A., Lagos-Cabré R., Kong M., Cárdenas A., Burgos-Bravo F., Schneider P., et al. (2016). Integrin-mediated transactivation of P2X7R via hemichannel-dependent ATP release stimulates astrocyte migration. Biochim. Biophys. Acta 1863 2175–2188. 10.1016/j.bbamcr.2016.05.018 - DOI - PubMed
    1. Arican O., Aral M., Sasmaz S., Ciragil P. (2005). Serum levels of TNF-α, IFN-γ, IL-6, IL-8, IL-12, IL-17, and IL-18 in patients with active psoriasis and correlation with disease severity. Mediators Inflamm. 2005 273–279. 10.1155/mi.2005.273 - DOI - PMC - PubMed
    1. Astro V., De Curtis I. (2015). Plasma membrane-associated platforms: dynamic scaffolds that organize membrane-associated events. Sci. Signal. 8:re1. 10.1126/scisignal.aaa3312 - DOI - PubMed
    1. Avalos A. M., Arthur W. T., Schneider P., Quest A. F. G., Burridge K., Leyton L. (2004). Aggregation of integrins and RhoA activation are required for Thy-1-induced morphological changes in astrocytes. J. Biol. Chem. 279 39139–39145. 10.1074/jbc.M403439200 - DOI - PubMed
    1. Avalos A. M., Valdivia A. D., Munoz N., Herrera-Molina R., Tapia J. C., Lavandero S., et al. (2009). Neuronal Thy-1 induces astrocyte adhesion by engaging syndecan-4 in a cooperative interaction with αvβ3 integrin that activates PKCα and RhoA. J. Cell Sci. 122 3462–3471. 10.1242/jcs.034827 - DOI - PMC - PubMed

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