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(The FASEB Journal. 2006;20:1045-1054.)
© 2006 FASEB

Thy-1 as a regulator of cell-cell and cell-matrix interactions in axon regeneration, apoptosis, adhesion, migration, cancer, and fibrosis

Tanya A. Rege and James S. Hagood1

The Departments of Cell Biology and Pediatrics and the Medical Scientist Training Program at the University of Alabama at Birmingham, Birmingham, Alabama, USA

1Correspondence: Department of Pediatrics & Cell Biology, The University of Alabama at Birmingham, VH 648A, 1670 University Blvd., Birmingham, AL 35294-0019, USA. E-mail: jhagood{at}peds.uab.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 NON-IMMUNOLOGIC FUNCTIONS OF THY...
 REGULATION OF THY-1 EXPRESSION
 CONCLUSIONS
 REFERENCES
 
Thy-1 (CD90) is a 25–37 kDa glycosylphosphatidylinositol (GPI) -anchored glycoprotein expressed on many cell types, including T cells, thymocytes, neurons, endothelial cells, and fibroblasts. Activation of Thy-1 can promote T cell activation, and this role of Thy-1 is reviewed elsewhere. Thy-1 also affects numerous nonimmunologic biological processes, including cellular adhesion, neurite outgrowth, tumor growth, migration, and cell death. In reviewing the nonimmunologic functions of Thy-1, we discuss the phenotype of the Thy-1 null mouse, signaling pathways modulated by Thy-1, the role of the GPI anchor in Thy-1 localization to lipid rafts and signaling, and regulation of Thy-1 expression. Thy-1 is an important regulator of cell-cell and cell-matrix interactions, with important roles in nerve regeneration, metastasis, inflammation, and fibrosis.—Rege, T. A., Hagood, J. S. Thy-1 as a regulator of cell-cell and cell-matrix interactions in axon regeneration, apoptosis, adhesion, migration, cancer, and fibrosis.


Key Words: neurite outgrowth • tumor suppressor • GPI anchor • wound healing


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
NON-IMMUNOLOGIC FUNCTIONS OF THY...
 REGULATION OF THY-1 EXPRESSION
 CONCLUSIONS
 REFERENCES
 
THY-1 (CD90) IS 25–37 kDa GPI-anchored protein found on the external leaflet of the lipid bilayer, localizing to lipid rafts. Thy-1 maps to chromosome 9 in mice, and human Thy-1 maps to chromosome 11q22.3 (1 , 2) . There are two alleles in mice, which code for Thy-1.1/CD90.1 and Thy-1.2/CD90.2, and differ by one amino acid. CD90.2 is expressed by most strains of mice, whereas CD90.1 is expressed by AKR/J and PL mouse strains (1 , 3) . Thy-1 is expressed on human fibroblasts, neurons, blood stem cells, and endothelial cells, as well as murine T cells (3 4 5 6) . Thy-1 is involved in T cell activation (7) ; the immunological roles of Thy-1 were recently reviewed elsewhere (3) . Thy-1 also has widespread nonimmunologic functions including inhibition of neurite outgrowth, apoptotic signaling, leukocyte and melanoma cell adhesion and migration, tumor suppression, and fibroblast proliferation and migration. Taken together, these functions indicate that Thy-1 is an important regulator of cell-cell and cell-matrix interactions.

Some of the functions of Thy-1 in vivo have been assessed using the Thy-1 knockout mouse (Table 1 ). Thy-1 null mice are viable and appear neurologically normal, but display excessive GABAergic inhibition in the dentate gyrus and regional inhibition of long-term potentiation (8 , 9) . Furthermore, these mice do not base their food choices on learned socially transmitted cues. Although Thy-1 null mice display normal social interactions and normal learning in a maze, they fail to learn from other mice which foods are safe to eat as compared to wild-type mice. Failure to learn from social cues is rescued after transgenic expression of Thy-1 or pharmacologic treatment with a GABA (A) receptor antagonist (10) . These data suggest that Thy-1 may regulate GABAergic inhibition of neurotransmission, which may affect the ability to learn from socially transmitted cues. The phenotype of the Thy-1 null mice also includes impaired cutaneous immune responses and abnormal retinal development (11 , 12) . In Thy-1 null mice, the inner nuclear, inner plexiform, ganglion cell, and outer segment layers of the retina are thinner than in wild-type control mice (12) . Complete phenotypic characterization of the Thy-1 null mouse, and assessment of its disease susceptibility, are still lacking. However, a large number of functions for Thy-1 have been described in a variety of interesting studies over several decades.


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  		Table 1. Phenotype of Thy-1 knockout mouse


   NON-IMMUNOLOGIC FUNCTIONS OF THY-1
TOP
 ABSTRACT
 INTRODUCTION
 NON-IMMUNOLOGIC FUNCTIONS OF THY...
REGULATION OF THY-1 EXPRESSION
 CONCLUSIONS
 REFERENCES
 
Thy-1 modulates neurite outgrowth
Thy-1 is highly expressed on adult neurons. Using an ELISA, Thy-1 is detected in the rat brain at highest concentrations in the striatum and hippocampus, followed by the neocortex, cerebellum, spinal cord, and the retina and optic nerve (13) . One study compared Thy-1 expression in four human neuronal cell lines, two neuroglial cell lines, and fresh tumor cells of neuronal origin. Three of the four neuronal cell lines, all of the neuroglial cell lines, and 80% of the tumors are strongly positive for Thy-1 (14) . After fractionation of the adult mouse brain, Thy-1 is largely expressed in the cerebral cortex in synaptosomes as compared to mitochondria, neurons, and myelin (15) .

Expression of Thy-1 in a neural cell line inhibits neurite outgrowth over a substratum of mature astrocytes, but not over Schwann cells or embryonic glial cells (16) . These data suggest that Thy-1 may function to stabilize neuronal synapses and block neuronal repair in astrocyte-rich regions of the brain (16) . Neurite outgrowth is important for neuronal growth and synapse formation. As axons cannot repair, understanding the molecular signaling in neurite outgrowth is important for the treatment of brain and spinal cord injuries, as well as neurodegenerative diseases (17) . Inhibition of neurite outgrowth can be reversed by the addition of soluble Thy-1. As the neuronal expression of Thy-1 is developmentally regulated and altered after injury (18 19 20) , these data suggest that the interaction between Thy-1 on neurons and astrocytes may be important in blocking axon regeneration after neuronal injury (16) . However, Thy-1 knockout mice develop grossly normal brains and spinal cords, and these mice do not regenerate axons after spinal cord injury. Although these data suggest Thy-1 is not absolutely required for nervous system development or for inhibiting axonal regeneration (21) , it may have an important role in generating the neuronal network.

Thy-1 complexes with G inhibitory proteins, the Src family kinase (SFK) member c-fyn, and tubulin within lipid rafts in chick forebrain cells. Incubation of these cells with a Thy-1 antibody (Ab) resulted in increased interactions between Thy-1, G inhibitory proteins, c-fyn, and tubulin, but a decrease in kinase activity and phosphoprotein content within the lipid rafts (22) . Therefore, Thy-1 may regulate the function of these proteins, resulting in reorganization of the cytoskeleton and the modulation of migration necessary for neurite outgrowth.

A ligand for Thy-1 on astrocytes was identified (23) . Thy-1 engagement of the ß3 integrin on astrocytes induces focal adhesion kinase (focal adhesion kinase F-actin (FAK)), p130Cas, and RhoA activation and the recruitment of paxillin, vinculin, and FAK to focal contacts, promoting focal adhesion and stress fiber formation (24 , 25) . Furthermore, as inhibition of neurite outgrowth occurs only in Thy-1-expressing neurons propagated over astrocytes, the interaction of neuronal Thy-1 with ß3 on astrocytes may promote bidirectional signaling, inhibiting neurite outgrowth (24 , 26) (Fig. 1 ).


Figure 1
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  		Figure 1. Bidirectional signaling activated by the interaction between Thy-1 on neurons and integrin ß3 on astrocytes. After an interaction between integrin ß3 and Thy-1, FAK, p130Cas, vinculin, paxillin, and RhoA are activated, promoting focal adhesion and stress fiber formation in astrocytes. This interaction may also be necessary for the inhibition of neurite outgrowth over astrocytes (24 25 26) .

There is also evidence that Thy-1 activation promotes neurite outgrowth. Addition of an anti-Thy-1 Ab can promote neurite outgrowth; cleavage of cell surface Thy-1 by the addition of phospholipase C blocks this effect. This promotion of neurite outgrowth by Thy-1 is dependent on G{alpha}i and L- and N-type calcium channel activation (27) . An unidentified Thy-1 binding protein on astrocytes is necessary for Thy-1-induced neurite outgrowth (23) .

The importance of the GPI anchor of Thy-1 in signaling has been studied in neurons. The presence of the GPI anchor affects the conformation of Thy-1 (28 , 29) . The GPI anchor of Thy-1 is also required for localization to lipid rafts. Cells expressing a Thy-1 construct in which the GPI anchor is replaced with the transmembrane domain of CD8 were unable to block neurite outgrowth. Thy-1 lacking the GPI anchor does not localize to the same membrane microdomains as wild-type Thy-1, suggesting the GPI anchor is necessary for localization of Thy-1 to specific lipid raft microdomains (30) . Furthermore, using monovalent immunogold labeling and immunoaffinity isolation of lipid rafts, Thy-1 and the GPI-anchored prion protein traffic to different subsets of lipid rafts, which differ in lipid composition (31 , 32) . Thy-1 has three N-glycosylation sites, and the GPI anchor has also been found to affect glycosylation. When soluble recombinant Thy-1 and recombinant GPI-anchored Thy-1 are expressed in Chinese hamster ovary cells, site occupancy is reduced in the soluble protein (33) .

Thy-1 promotes cell death in thymocytes and mesangial cells
Treatment of malignant mouse T lymphoma CS-21 cells with an anti-Thy-1 Ab increases intracellular free calcium levels and induces apoptosis. The Ab induces apoptosis despite up-regulation of the antiapoptotic bcl-2 protein (34) . One study used two different Thy-1 antibodies to induce apoptosis in thymocytes. Monoclonal anti-Thy-1 (G7) could aggregate and induce apoptosis alone, but monoclonal anti-Thy-1 (MCS-34) could not aggregate and could only induce apoptosis after cross-linking with secondary antibodies. After treatment with G7 or cross-linked MCS-34, CPP32-like proteases are activated and the expression levels of antiapoptotic bcl-2 family members (bcl-2 and bcl-XL) are decreased (35) . These data suggest that Thy-1 must aggregate in order to signal thymocyte apoptosis. Anti-Thy-1 Ab induces apoptosis of Thy-1-transfected thymoma cells through a mechanism requiring new transcription and translation, unlike the mechanism in thymocytes (36) .

Thy-1 antibodies also induce apoptosis in vivo. Injection of an anti-Thy-1 Ab into rats induces kidney mesangial cell death and the development of glomerulonephritis. This cell death was identified as apoptosis, as anti-Thy-1 induces DNA fragmentation in mesangial cells in vitro and in glomeruli harvested from rats in vivo (37) . Incubation of rat glomerular mesangial cells with an anti-Thy-1 Ab or its F(ab')2 fragments induces apoptosis in 19–34% of cells, as detected by TUNEL staining or annexin V staining, and treatment with cross-linked anti-Thy-1 Ab induces apoptosis more efficiently than treatment with the monomeric Ab (38 , 39) . After treatment of mesangial cells with anti-Thy-1 antibodies, inositol triphosphate and intracellular calcium levels are increased through a mechanism requiring protein tyrosine kinases (40) .

The cell death induced by Thy-1 is not necessarily apoptotic. A study using electron microscopy found that treatment of glomerular mesangial cells with an anti-Thy-1.1 Ab induces necrosis, not apoptosis. Although chromatin condensation is detected, nuclear membrane disruption, cellular swelling, and organelle degradation are seen. This phenotype is consistent with necrosis. Furthermore, acute inflammation is detected as there is no phagocytosis of dead cells (41) . As the injection of Thy-1 antibodies into rats is used as a model for mesangial proliferative glomerulonephritis (42 , 43) , Thy-1 may contribute to the development of glomerulonephritis by inducing mesangial cell death.

Thy-1 is a tumor suppressor in ovarian cancer and nasopharyngeal carcinoma
The transfer of chromosome 11 into the human ovarian cancer cell line SKOV-3 suppresses tumor growth in immunodeficient mice. Thy-1 is expressed only in nontumorigenic cell clones; thrombospondin-1 (TSP-1), a secreted protein acidic and rich in cysteine (SPARC), and fibronectin are also up-regulated in nontumorigenic clones. TSP-1, SPARC, and fibronectin are not expressed in SKOV-3 cells, and their expression levels are likely regulated by gene(s) on chromosome 11 (44) . As fibronectin expression is lost in tumors and angiogenesis is required for tumor growth and metastasis (45 , 46) , Thy-1 could potentially inhibit tumor growth by up-regulating the expression levels of fibronectin and TSP-1.

The role of Thy-1 in nasopharyngeal carcinoma (NPC) was investigated recently. Thy-1 expression is decreased or lost in multiple NPC cell lines, 65% of NPC samples, and 63% of lymph node metastatic NPC tumors. Restoration of Thy-1 expression in NPC HONE1 cells decreases colony formation. Loss of Thy-1 expression appears to be due to promoter hypermethylation in NPC cell lines (47) . These data suggest that Thy-1 may function as a tumor suppressor in ovarian cancer and NPC.

Thy-1-transfected SKOV-3 cells injected subcutaneously (s.c.) into SCID mice form tumors that are smaller and less proliferative than tumors formed after the injection of wild-type SKOV-3 cells. Transfection of antisense Thy-1 vectors into a nontumorigenic clone restored tumorigenicity, indicating Thy-1 is a putative tumor suppressor gene for human ovarian cancer (48) . To investigate how Thy-1 modulates tumor growth, a tetracycline-inducible system for Thy-1 expression in SKOV-3 cells was established. After Thy-1 induction, fibronectin and antiangiogenic thrombospondin-1 are up-regulated. However, SPARC expression is not affected by Thy-1 (49) .

Thy-1 promotes transendothelial cell migration of leukocytes and melanoma cells
Thy-1 promotes adhesion of thymocytes to thymic epithelium, leukocytes, and monocytes to endothelial cells and fibroblasts, and melanoma cells to endothelium (50 51 52) . Thy-1 can interact with {alpha}vß3 on melanoma cells, and {alpha}Xß2 and {alpha}Mß2 integrins on leukocytes (24 , 53 54 55) . Thy-1 was identified on endothelial cells and fibroblasts, and an unknown Thy-1 ligand was identified on polymorphonuclear leukocytes and monocytes. This Thy-1 ligand was involved in adhesion of monocytes and polymorphonuclear leukocytes to endothelial cells and fibroblasts (51) . The Thy-1 ligand on leukocytes was identified as the integrin {alpha}Mß2, and the interaction between Thy-1 and {alpha}Mß2 is necessary for the transendothelial cell migration of human leukocytes, suggesting Thy-1 may play a role in leukocyte recruitment and extravasation during inflammation (55) .

Thy-1 is also expressed on activated endothelial cells, particularly microvascular endothelial cells within melanoma and melanoma metastases. A Thy-1 ligand was detected on melanoma cells, which mediated adhesion of melanoma cells to the Thy-1-expresssing endothelium (52) . This Thy-1 ligand is likely {alpha}vß3, as the interaction between Thy-1 on dermal MvEC and {alpha}vß3 on melanoma cells is necessary for melanoma cell adhesion and migration of melanoma cells across an endothelial cell monolayer (54) . These data suggest a role for Thy-1 in regulating cell adhesion necessary for melanoma invasion and metastasis.

Thy-1 modulates the fibroblast phenotype relevant to wound healing and fibrosis
Normal pulmonary fibroblasts are heterogeneous and can be divided into subpopulations on the basis of size and shape, cytokine profiles, lipid content, and cell surface protein expression (56 , 57) . The most extensively characterized in vitro model of fibroblast heterogeneity is based on the surface expression of Thy-1 (57 , 58) . Thy-1 may play a role in wound repair and fibrosis, and Thy-1 protein expression in human fibroblasts from granulation tissue is up-regulated on days 3–6 postinjury (59) .

Pulmonary fibroblasts sorted on the basis of Thy-1 expression differ in expression of and response to cytokines and growth factors (57 , 60 61 62 63) . Thy-1 (+) splenic fibroblasts produce greater levels of interleukin 6 (IL-6), whereas only Thy-1 (–) fibroblasts express class II major histocompatibility complex (MHC) antigens after IFN-{gamma} treatment (58 , 64) . After tumor necrosis factor (TNF) {alpha} stimulation, only Thy-1 (–) murine pulmonary fibroblasts produce IL-1 (65) . Thy-1 (–) pulmonary fibroblasts secrete more latent TGF-ß than Thy-1 (+) fibroblasts, and only Thy-1 (–) fibroblasts are able to activate latent TGF-ß in response to fibrogenic stimuli (66 , 67) . Thy-1 (–) rat pulmonary fibroblasts express platelet-derived growth factor {alpha} (PDGF-{alpha}) receptor at higher levels than Thy-1 (+) fibroblasts, and only Thy-1 (–) fibroblasts are responsive to PDGF-AA-induced proliferation (61) .

Thy-1 expression also affects fibroblast proliferation. Although Thy-1 (–) and (+) pulmonary fibroblasts secrete similar levels of IL-1 receptor antagonist (IL-1Ra), Thy-1 (–) fibroblasts accumulate higher levels of IL-1Ra. IL-1Ra-containing conditioned media from fibroblasts inhibits concanavalin A- or IL-1 beta-induced proliferation of a T cell clone (68) . On the other hand, Thy-1 (–) fibroblasts appear more sensitive to IL-1 beta stimulation, as IL-1 beta treatment up-regulates PDGF{alpha}R in only Thy-1 (–) pulmonary fibroblasts. Furthermore, after IL-1 beta treatment Thy-1 (–) cells have increased proliferation and IL-6 expression compared to Thy-1 (+) cells (60) .

The original description of Thy-1 subpopulations in fibroblasts indicated significant differences in cellular morphology. Thy-1 (–) murine pulmonary fibroblasts have a more polygonal morphology than the more spindle-shaped Thy-1 (+) fibroblasts, and a more well-established microfilament and microtubule cytoskeleton (58) (Table 2 ). These differences have been attributed to Thy-1-associated signaling, as Thy-1 expression has been found to affect cell-matrix adhesions, stress fiber formation, and migration. Naturally occurring Thy-1 (+) pulmonary fibroblasts or fibroblasts transfected with Thy-1 form longer, more numerous focal adhesions and well-organized actin stress fibers, whereas Thy-1 (–) cells form small peripheral focal adhesions and fewer stress fibers (63) .


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  		Table 2. The effect of Thy-1 on the cytoskeleton of pulmonary fibroblasts

As Thy-1 (–) cells have fewer focal adhesions and stress fibers, Thy-1 (–) lung fibroblasts are more migratory at baseline using in vitro wound healing assays. Thy-1 modulates adhesion and migration by inhibiting SFK activation and decreasing phosphorylation of p190 Rho GTPase-activating protein, resulting in activation of RhoA (63) . Focal adhesions are regulated by factors controlling their disassembly as well as their formation. The matricellular protein TSP-1 and a 19 amino acid sequence from the amino-terminal/heparin binding domain of TSP-1 (hep I) induces focal adhesion disassembly and promotes migration of fibroblasts (69) . Thy-1 surface expression, phosphoinositide (PI) 3-kinase activation, SFK activation, and integrity of lipid rafts are required for TSP-1/hep I-mediated focal adhesion disassembly of pulmonary fibroblasts (70) .

The differences in cytokine and growth factor responses and cellular migration in Thy-1 subpopulations suggest that Thy-1 expression may affect the function of fibroblasts in wound healing and fibrosis. Thy-1 subpopulations display differential matrix production. Both Thy-1 (+) and (–) pulmonary fibroblasts synthesize fibronectin, but some Thy-1 (+) clones were found to produce 2- to 3-fold more collagen (71) . Thy-1 (–) lung fibroblasts produce more latent TGF-ß1 than do Thy-1 (+) fibroblasts (66) , and only Thy-1 (–) fibroblasts are able to activate latent TGF-ß, resulting in increased production of fibronectin in response to fibrogenic stimuli (67) . The role of Thy-1 in modulating fibrosis has been supported in vivo. After bleomycin-induced injury, Thy-1 null mice develop more extensive and severe lung fibrosis than do wild-type mice. Within the fibrotic lesions of bleomycin-treated wild-type mice, myofibroblastic cells with active TGF-ß were predominantly Thy-1 (–). In tissue sections from human idiopathic pulmonary fibrosis patients, myofibroblastic cells within fibroblastic foci, which are collections of activated fibroblasts in the lung whose presence is inversely correlated to survival, are predominantly Thy-1 (–) (72) .

Myofibroblasts are contractile fibroblasts that express {alpha}-smooth muscle actin and are present transiently in early wound healing, but persist in many fibrotic lesions (73 , 74) . The role of Thy-1 in myofibroblastic differentiation is unclear. After injury of the cornea, keratocytes transform into corneal fibroblasts or myofibroblasts. After treatment of human corneal keratocytes with serum or TGF-ß to induce differentiation into fibroblasts or myofibroblasts, respectively, Thy-1 expression is induced (75) . This suggests that Thy-1 expression is important in corneal wound repair. During wound repair, myofibroblasts are responsible for wound contraction (76) . Using human myometrial and orbital fibroblasts sorted on the basis of Thy-1 expression, only Thy-1 (+) fibroblasts differentiate into myofibroblasts, as they display {alpha} smooth muscle actin ({alpha}-SMA) expression after treatment with TGF-ß or supernatant from platelet concentrate, whereas only Thy-1 (–) fibroblasts differentiate into lipofibroblasts, as assessed by accumulation of cytoplasmic lipid droplets after treatment with the PPAR{gamma} ligand 15-deoxy-delta (12,14) PGJ2 (77) . On the other hand, in murine lung fibroblasts the Thy-1 (–) subset have higher {alpha}-SMA expression at baseline and in response to TGF-ß activation (67) , and stimulation of human pulmonary fibroblasts with IL-1 and TNF{alpha} promotes loss of Thy-1 expression associated with differentiation to a myofibroblast phenotype (72) . The different roles observed for Thy-1 in promoting myofibroblast differentiation and fibrosis may be tissue specific, as Thy-1 expression appears to promote myofibroblast differentiation in fibroblasts isolated from myometrial and orbital tissue, yet inhibits myofibroblast differentiation in fibroblasts derived from pulmonary tissue.


   REGULATION OF THY-1 EXPRESSION
TOP
 ABSTRACT
 INTRODUCTION
 NON-IMMUNOLOGIC FUNCTIONS OF THY...
 REGULATION OF THY-1 EXPRESSION
CONCLUSIONS
 REFERENCES
 
The expression of Thy-1 is developmentally and spatially regulated. During early development, neuronal expression of Thy-1 is low. After maturation, Thy-1 expression is increased in neurons (18 , 78) . In rats and mice, Thy-1 protein is present on the cell body and dendrites of neurons but is not expressed on axons until axonal growth is complete (79) . Expression of Thy-1 is also affected by injury. Two days postcrush injury of the sciatic nerve, Thy-1 expression in dorsal root ganglia is decreased and returns between days 4 and 7 (19) . Thy-1 mRNA expression, as assessed by RNase protection assays and in situ hybridization, is also down-regulated after optic nerve crush or intravitreal injection of N-methyl-D-aspartate (20) .

Thy-1 expression is also regulated during ovarian development. Although Thy-1 is continuously expressed in the fallopian tube tunica propria, high levels of Thy-1 are expressed in the theca interna of growing antral follicles and developing corpora lutea (80) . Thy-1 is released by vascular pericytes in the ovaries during follicular differentiation (80 , 81) . This decrease in Thy-1 occurs concurrently with the appearance of macrophages in the follicular antrum. It will be interesting to determine whether the recruited macrophages are a source of proteases and cytokines that may stimulate Thy-1 shedding.

Thy-1 expression differs by species, and this may be due to transcriptional regulation. In mice, Thy-1 is expressed on thymocytes and splenocytes, but is only expressed on thymocytes in rats. The third intron of the mouse Thy-1 gene contains a 36 base pair region that can bind nuclear transcription factors, such as Ets-1-like NF, which is expressed in thymocytes and splenocytes. The homologous 36 base pair region of the rat Thy-1 gene does not contain the Ets-1-like NF binding site, but binds another NF that is expressed in rat thymocytes but not splenocytes. Also, hyperthmethylation may lead to decreased or absent Thy-1 expression in NPC cell lines (47) .

There is also evidence of post-transcriptional regulation of Thy-1 expression. Thy-1 mRNA expression is rapidly followed by protein expression in rat cerebellum and rat and mouse cerebrum, whereas a delay of several days occurs between Thy-1 mRNA and protein expression in mouse Purkinje cells, indicating post-transcriptional regulation of Thy-1 expression (82) . Post-transcriptional regulation of Thy-1 may be due to a widely expressed transacting suppressor protein, as Thy-1.1 expression is down-regulated in heterokaryons constructed with Thy-1.1-expressing mouse T cells and Thy-1.2-expressing mouse neurons (83) . Therefore, the secreted suppressor of Thy-1 in neurons can also inhibit Thy-1 expression on T cells and is not tissue specific.

Iron levels also affect Thy-1 expression. Iron chelation in pheochromocytoma cells propagated in vitro down-regulates Thy-1 expression. In vivo, rats fed an iron-deficient diet and tissue sections of the substantia nigra from patients with Restless Legs Syndrome, which is characterized by decreased iron levels in the substantia nigra, display decreased expression of Thy-1 (84) . Thy-1 expression may be regulated by protein shedding (85 , 86) . Elevated levels of soluble Thy-1 are detected in the serum and inflamed synovial fluid of patients with venous leg ulcers (5) . Cytomegalovirus infection down-regulates Thy-1 expression on human dermal fibroblasts through a mechanism that likely involves shedding and requires cytomegalovirus immediate-early/early gene products (87) . Inflammatory cytokines such as IL-1ß and TNF{alpha} induce shedding of Thy-1 from human lung fibroblasts associated with myofibroblastic differentiation (72) .


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 NON-IMMUNOLOGIC FUNCTIONS OF THY...
 REGULATION OF THY-1 EXPRESSION
 CONCLUSIONS
REFERENCES
 
Thy-1 is a GPI-anchored protein with a number of biological effects involving cell-cell and cell-matrix interactions and cell motility. Well-described effects of its expression include inhibition of neurite outgrowth and regulation of cell death (Table 3 ). Expression of Thy-1 also affects the morphology, proliferation, migration, and differentiation of fibroblasts. Thy-1 may also function as a tumor suppressor in ovarian cancer yet promote melanoma migration and metastasis. Therefore, Thy-1 signaling may have important roles in development, tissue responses to injury, and oncogenesis.


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  		Table 3. Non-immunologic functions of Thy-1

Thy-1 signaling pathways
Thy-1 signaling can involve interactions with ß1 and ß3 integrins (53 54 55) . Interactions between Thy-1 and integrins are necessary for the migration of leukocytes and melanoma cells across an endothelial cell monolayer, suggesting Thy-1 may be important for melanoma metastasis and leukocyte recruitment. The interaction of Thy-1 on neurons with ß3 on astrocytes may trigger a bidirectional signaling cascade. After engagement of ß3 by Thy-1, astrocytes have increased recruitment of FAK, paxillin, vinculin, and p130Cas to focal adhesions (24) . Furthermore, the activation of Thy-1 after an interaction with ß3 on astrocytes may inhibit neurite outgrowth over astrocytes.

Thy-1 also signals through nonreceptor tyrosine kinases, such as SFK. Thy-1 is reported to interact with the SFK members fyn and lyn (88 , 89) . SFK is transiently activated in Thy-1 (+), not Thy-1 (–), cells after treatment with TSP-1, and Thy-1 expression and SFK activation are required for TSP-1-induced focal adhesion disassembly. After T cell receptor activation, thymocytes isolated from Thy-1 null mice have increased activity of the SFK member lck and cell proliferation compared with wild-type mice, suggesting that Thy-1 may inhibit T cell receptor-induced SFK activation and proliferation of thymocytes by sequestering SFK (90) .

As Thy-1 is a GPI-anchored protein, the exact mechanism by which the signal is transduced from Thy-1 to SFK remains unclear. Thy-1 may interact with SFK through an adapter protein. In T cells, coactivation of CD3 and Thy-1 triggers phosphorylation of the transmembrane adapter protein linker for activation of T cells (LAT), which is found in lipid rafts (91) . In thymocytes, Thy-1 coimmunoprecipitates with an 85–90 kDa phosphoprotein that contains a binding site for SH2 domain-containing proteins, such as fyn, csk, phosphatidylinositol 3'-kinase, rasGAP, vav, and lck (92) . Alternatively, the GPI anchor of Thy-1 may directly interact with palmitoylated cysteines on SFK (Fig. 2 ). Site-directed mutagenesis of palmitoylation sites on the SFK members lck and fyn inhibits the interaction between SFK and the GPI-anchored proteins CD55 and CD59 (93) .


Figure 2
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  		Figure 2. Potential mechanisms of signal transduction from Thy-1 to Src family kinases. Thy-1 is reported to interact with the SFK members fyn and lyn (88 , 89) . As the GPI anchor of Thy-1 does not span the cell membrane, there are two potential mechanisms by which Thy-1 may activate SFK: the GPI anchor of Thy-1 may directly interact with palmitoylated cysteines of SFK (A) or Thy-1 may signal to SFK through an intermediate transmembrane adapter protein (B). In support of the latter model, Thy-1 coimmunoprecipitates with an 85–90 kDa transmembrane phosphoprotein that contains a binding site for SH2 domain-containing proteins (92) .

Clinical implications for Thy-1
Thy-1 affects diverse physiological and pathological processes. Thy-1 expression is developmentally and spatially regulated and limited to adult nerve axons. In vitro, Thy-1 blocks neurite outgrowth. Therefore, Thy-1 may function as a "stop signal" in neuronal development. As such, Thy-1 may prevent regeneration of nerves after injury. Thy-1 also appears to function as a tumor suppressor in ovarian cancer and NPC. Thy-1 expression in an ovarian cancer cell line up-regulates TSP-1 and fibronectin levels, which could prevent tumor angiogenesis and metastasis. It will be interesting to investigate whether Thy-1 null mice are more susceptible to tumor growth and metastasis.

Activation of Thy-1 induces apoptosis or cell death of glomerular mesangial cells in vitro and in vivo. Furthermore, treatment of rodents with a Thy-1 Ab induces apoptosis of the glomerulus and promotes glomerulonephritis. These data suggest that the role of Thy-1 in the progression of mesangial proliferative glomerulonephritis warrants further investigation. As Thy-1 promotes migration of leukocytes, melanoma cells, and TSP-1-induced fibroblasts, Thy-1 signaling may be crucial for leukocyte recruitment, melanoma metastasis, and fibroblast recruitment to a wound site. Last, Thy-1 expression on fibroblasts may affect wound healing and fibrosis. Thy-1 null mice are more sensitive to bleomycin-induced lung fibrosis, and fibroblasts within the fibroblastic foci of idiopathic pulmonary fibrosis patients are predominantly Thy-1 (–). The role of Thy-1 in myofibroblast differentiation is less clear and may be tissue specific. Taken together, these data suggest a complex role for Thy-1 in multiple biological processes. Its immunoglobulin domain structure suggests that it may function in a ligand binding capacity. The heterotypic interactions with beta integrins are consistent with this role and may be critical to Thy-1’s effects on cell-cell and cell-matrix interactions. Because of its location in lipid rafts, Thy-1 is well positioned to affect the formation of signaling complexes. This role is supported by effects of Thy-1 cross-linking on tyrosine kinase signaling relevant to cell adhesions, cytoskeletal regulation, and immune signaling. The biological importance of Thy-1 is supported by its evolutionary conservation, its developmental regulation, and by multiple mechanisms for controlling its expression at the transcriptional and post-transcriptional levels by shedding. Thy-1 signaling could potentially be modulated to treat diseases such as glomerulonephritis, nerve damage, cancer, and fibrosis.

Future directions
Although there have been many recent advances regarding the role of Thy-1, many questions remain to be answered. For example, the exact mechanism by which Thy-1 signals is unclear. Whether Thy-1 directly interacts with cytoplasmic tyrosine kinases or indirectly interacts with these signaling molecules via a signaling complex needs to be investigated. The interaction of Thy-1 with integrins also poses many crucial questions, such as whether or not Thy-1 promotes melanoma metastasis and leukocyte extravasation in vivo. Thy-1 seems to have a contradictory effect in other tumor types. In ovarian cancer and nasopharyngeal cancer and metastses, Thy-1 inhibits tumor growth through an unknown mechanism. It will be interesting to determine whether Thy-1 affects transendothelial cell migration or induces apoptosis of ovarian and nasopharyngeal cancer cells. The role of Thy-1 in fibrosis also warrants further investigation, particularly the signaling pathways by which Thy-1 modulates fibroblast differentiation, migration, and apoptosis. The role of Thy-1 in disease could be further investigated through phenotypic studies using Thy-1 null mice.


   ACKNOWLEDGMENTS
 
Supported in part by National Institutes of Health (NIH) grant HL065348 to J.S.H. and fellowship NS49674 to T.A.R., and Research Facilities Improvement Program Grant No. C06 RR 15490 from the National Center for Research Resources.

Received for publication November 22, 2005. Accepted for publication January 19, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 NON-IMMUNOLOGIC FUNCTIONS OF THY...
 REGULATION OF THY-1 EXPRESSION
 CONCLUSIONS
 REFERENCES
 

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