Chapter Four - Thy-1-Interacting Molecules and Cellular Signaling in Cis and Trans

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Abstract

Thy-1, discovered almost 50 years ago, was for many years a subject of great scientific interest. The putative functions attributed to this molecule could not be confirmed due, at least in part, to a ligand that took a long time to be identified. This chapter describes the properties of Thy-1 and the regulation of its expression. Also, the interactions that have been described for Thy-1 in both cis and trans, and the signaling mechanisms reported to emanate from such interactions are discussed. The consequences of Thy-1-activated signaling pathways for different cell types and organisms are also reviewed. Since the discovery of αVβ3 integrin as a receptor for Thy-1 in astrocytes, many more functions have been attributed to Thy-1 interactions in trans toward other cell types. Recently, a ligand for neuronal Thy-1 was unveiled and shown to elicit signaling in cis. The ligand and the receptor for Thy-1 turned out to be the same molecule, αVβ3 integrin, which upon interaction with Thy-1 yields bidirectional astrocyte-to-neuron communication. Thus, Thy-1 biology is again beginning to make progress in answering main questions surrounding this enigmatic molecule. Some of these remaining questions are highlighted in this chapter.

Introduction

Thy-1 is a small glycoprotein that faces the extracellular matrix (ECM) and is anchored to the outer leaflet of the plasma membrane through a glycosyl-phosphatidylinositol (GPI) moiety. Thy-1 was one of the earliest GPI-anchored proteins to be sequenced and purified. Insights gained from the study of this protein permitted characterization of the molecular sequence of events by which the GPI moiety is added to proteins and how this posttranslational modification anchors proteins to the exoplasmic leaflet of the cell membrane (Beghdadi-Rais et al., 1993, Conzelmann et al., 1987, Ferguson and Williams, 1988, Low and Kincade, 1985, Tse et al., 1985).

Pioneering studies also established that the Thy-1 protein core is composed of 110 amino acids and that carbohydrate modifications contribute to an additional 30% of Thy-1 mass (Williams et al., 1977). Subsequent technical and conceptual progress helped elucidate Thy-1 carbohydrate composition, thereby contributing to our current understanding of posttranscriptional protein modifications via glycosylation (Luescher and Bron, 1985, Williams et al., 1993). Moreover, the characterization of Thy-1 expression has helped improve our understanding of fundamental immunological mechanisms, many aspects of central nervous system development, possible mechanisms explaining how cancer and blood cells reach distant sites, the differences between fibroblast subpopulations with distinct morphology and capacity to proliferate and differentiate, as well as, of the formation and function of cell membrane nano/microdomains in multiple cell types (Hagood et al., 2001, Koumas et al., 2002, Lang et al., 1998, Morris, 1985, Morris and Grosveld, 1989, Tiveron et al., 1994, Wandel et al., 2012, Wetzel et al., 2004, Williams, 1982). For all these reasons, Thy-1 surely deserves a privileged position in the history of modern cell biology.

As pointed out by the famous Chilean writer and poet Pablo Neruda “Love is so short and oblivion so long.” Likewise for Thy-1, “fame and glory” of the initial years was followed by many years of subdued interest, largely due to the absence of a “binding partner” that permitted critically evaluating functions ascribed to the molecule. Accordingly, during the past 20 years, Thy-1 has been employed as a marker of biochemically isolated lipid-enriched subcellular fractions, a model to evaluate single-molecule dynamics at the cell plasma membrane or, alternatively, the Thy-1 promoter was employed with the sole purpose of overexpressing a protein of interest in a cell-specific manner (Feng et al., 2000, Haeryfar and Hoskin, 2004, Morris et al., 2011).

On the other hand, a reduced community continued the search to identify its function and finally in 2001, Thy-1 was shown to mediate adhesion of neurons to astrocytes through a direct interaction in trans with the receptor αVβ3 integrin, which triggered cell-signaling events and profound morphological changes in astrocytes (Avalos et al., 2002, Avalos et al., 2004, Avalos et al., 2009, Henriquez et al., 2011, Hermosilla et al., 2008, Leyton and Quest, 2002, Leyton and Quest, 2004, Leyton et al., 2001). Later on, Thy-1–αVβ3 integrin interaction became the starting point for a series of reports showing interactions in trans of Thy-1 with a selective group of integrins as receptors (Choi et al., 2005, Saalbach et al., 2005, Saalbach et al., 2007, Wetzel et al., 2004, Wetzel et al., 2006).

Recently also, we reported that the glial receptor αVβ3 integrin acts as a Thy-1 ligand, triggering signaling events and morphological changes in neurons (Herrera-Molina et al., 2012). These findings not only support the paradigm of a bidirectional communication between neurons and astrocytes but have also spawned research efforts to define Thy-1 function in cells other than those of the nervous system. In this chapter, we summarize the Thy-1 literature with the objective of highlighting its unique combination of molecular features and expression patterns. Then, cis-interacting partners are analyzed, which might be part of a Thy-1-related signaling complex in particular lipid rafts. Finally, after mentioning some examples of in trans-interacting counterparts, we review proposed functions of Thy-1, many of which still await experimental confirmation. Due to space constraints and the vast body of existing literature on this topic, we apologize for not mentioning many excellent contributions to the story by colleagues that during many years have been loving and forgetting Thy-1.

Section snippets

Theta antigen

Thy-1 was first mentioned by Reif and Allen (1964). The authors were looking for specific antibodies that would recognize thymoma cells from AKR mice, but the antibodies produced in C3HeB/Fe mice also recognized normal thymus cells (Reif and Allen, 1964). They named it theta antigen after a suggestion from Amos group to assign Greek letters to the mouse antigens (Amos et al., 1963). Soon, this AKR antigen was found in thymus-derived lymphocytes, bone marrow cells, brain cells, and certain types

Thy-1 cis interactions occur in rafts

Thy-1 localizes in a subclass of cholesterol-enriched, noncaveolae domains called “rafts” by inserting the GPI group into the outer leaflet of the cell membrane. In general, rafts are formed by cholesterol, phosphatidylcholine, and sphingomyelin (Neumann et al., 2010, Quest et al., 2004). The rigid and bulky tetracyclic cholesterol structure interacts with other lipids to form 5–200 nm patches of limited stability in the ms-to-min time range (Kusumi et al., 2004, Kusumi et al., 2010). These

Trans-Interacting Thy-1 Molecules and Signaling

Available evidence indicates that Thy-1 interacts with specific molecules on the surface of target cells and induces a variety of physiological processes, such as adhesion of thymocytes to thymic epithelium, leukocyte/monocyte extravasation, and tissue transmigration (Fig. 4.4). In addition, Thy-1 has been linked to pathological conditions, such as atherosclerosis, glial scar formation, and cancer cell metastasis. In this section, we will focus on the physiological relevance of cell–cell

In fibroblasts

Fibroblasts constitute a multifunctional cell population with an established role in wound healing, tumor formation, and regulation of the immune response (Kalluri and Zeisberg, 2006, Tomasek et al., 2002). ECM proteins are deposited mainly by fibroblasts; in this manner, fibroblasts control many of their own cellular functions and also those of neighboring cells. Such cellular functions include, cell shape, adhesion, motility, and differentiation (Laurent et al., 2007, Midwood et al., 2004).

Concluding Remarks

Despite all these years of oblivion, Thy-1 has been able to recapture the scientific community's attention. Studies on Thy-1 are slowly revealing its function in different cell types and its potential importance in health and disease. Indeed, this molecule, which for a long time was believed to be only a marker for cell lineages, has exposed many more of its charms in the past 10 years.

Thy-1 is a molecule that is expressed abundantly in many cells and due to its similarities with the

Acknowledgments

L. L. is supported by FONDECYT 1110149; Fogarty International Center, National Institutes of Health, Award Number 5R03TW007810; Iniciativas Científicas Milenio: Biomedical Neuroscience Institute P09-015-F. A. Q. is supported by FONDECYT 1130250; Anillo ACT1111. R. H-M acknowledges fellowships from DAAD, the Journal of Cell Science, and the CAEN International Society for Neurochemistry; support from the COST action ECMNet and the State of Saxony-Anhalt, and the “European Regional Development

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