Engagement of CD99 triggers the exocytic transport of ganglioside GM1 and the reorganization of actin cytoskeleton

Yoon, Sang Soon; Jung, Kyung In; Choi, Yoon La; Choi, Eun Young; Lee, Im Soon; Park, Seong Hoe; Kim, Tae Jin

doi:10.1016/s0014-5793(03)00268-0

Cited by 21 publications

(23 citation statements)

References 31 publications

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“…Particularly intriguing are the similarities between CD47 and CD99. Both localize in membrane rafts, induce very rapid caspase-independent cell death apototosis, apparently mediated by a novel apoptotic pathway, and become associated with the actin cytoskeleton upon engagement (Pettersen et al, 1999;Alberti et al, 2002;Mateo et al, 2002;Yoon et al, 2003). In this study, we demonstrate that actin is a key regulator of CD99 functions, being required both for ES cell adhesion and death.…”

Section: Discussionsupporting

confidence: 52%

“…It was recently demonstrated that CD99 molecules locate within lipid rafts upon stimulation and that this localization is required for CD99 effects (Alberti et al, 2002;Yoon et al, 2003). CD99 ligation appears to generally upmodulate the expression of several other cell surface molecules (Aussel et al, 1993;Hahn et al, 1997;Choi et al, 1998;Wingett et al, 1999;Bernard et al, 2000;Yoon et al, 2003), including PS, TCR, MHC class I and II molecules, LFA-1 and ICAM-1, and induce their concentration at cell-cell contact sites. Overexpression was the result of their accelerated mobilization from cytosolic compartments to the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

“…Overexpression was the result of their accelerated mobilization from cytosolic compartments to the plasma membrane. Whether or not these molecules are involved in mediating CD99 functions is still a matter of debate (Bernard et al, 1995;Hahn et al, 1997;Kasinrerk et al, 2000;Kim et al, 2003;Yoon et al, 2003). In ES, the engagement of CD99 resulted in cell aggregation and rapid externalization of PS, which is part of an apoptotic stimulus that induces ES cell death.…”

Section: Discussionmentioning

confidence: 99%

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Molecular mechanisms of CD99-induced caspase-independent cell death and cell–cell adhesion in Ewing's sarcoma cells: actin and zyxin as key intracellular mediators

et al. 2004

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CD99 is a unique 32-kDa cell surface molecule with broad cellular expression but still poorly understood biological functions. In cancer cells, CD99 is highly expressed in virtually all Ewing's sarcoma (ES). Engagement of CD99 induces fast homotypic aggregation of ES cells and caspaseindependent apoptosis. In this study, we analysed signal transduction after CD99 engagement on ES cells. Findings obtained with selective inhibitors indicated that only actin cytoskeleton integrity was essential for cell-cell adhesion and apoptosis of ES cells. Indeed, CD99 stimulation induced actin repolymerization, further supporting the role of cytoskeleton in CD99 signaling. Gene expression profiling of ES cells after CD99 engagement showed modulation in the expression of 32 genes. Among the pool of upregulated genes reported to be involved in cell adhesion, we chose to analyse the role of zyxin, a cytoplasmic adherens junction protein found to play a role in the regulation of the actin cytoskeleton. Overexpression of zyxin after CD99 ligation was confirmed by real-time PCR and Western blot. Treatment of ES cells with zyxin antisense oligonucleotides inhibited CD99-induced cell aggregation and apoptosis, suggesting a functional role for this protein. Therefore, our findings indicate that CD99 functions occur through reorganization of cytoskeleton and identify actin and zyxin as the early signaling events driven by CD99 engagement.

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Molecular mechanisms of CD99-induced caspase-independent cell death and cell–cell adhesion in Ewing's sarcoma cells: actin and zyxin as key intracellular mediators

et al. 2004

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“…CD99 engagement increases intracellular transport of TCR and MHC molecules to the cell surface in thymocytes and elicits the exocytic transport of GM1 in Jurkat cells, accompanied by the rearrangement of actin cytoskeletons (Yoon et al, 2003). Furthermore, CD99 has been linked to the migration of monocytes (Schenkel et al, 2002) and to morphological changes in T and B cells Bernard et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

CD99 activates T cells via a costimulatory function that promotes raft association of TCR complex and tyrosine phosphorylation of TCR ζ

Kim

Ban

et al. 2007

Exp Mol Med

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We investigated the co-stimulatory role of a cellsurface protein, CD99. Co-ligation of CD99 and suboptimal CD3 induced T-cell activation to a level comparable to that obtained with optimal CD3 or CD3+CD28. We also noted concomitant enhancement of the earliest T-cell receptor (TCR) signaling events. In addition, co-ligation of CD99 and CD3 led to translocation of TCR complexes into the lipid raft, without concomitant migration of CD99 to the raft, and consequent enhancement of TCR ζ-mediated signal 1. These data demonstrate the unique properties of CD99 co-stimulation that distinguish this molecule from CD28 and other raft-resident costimulatory factors.Keywords: antigens; lymphocyte activation; receptors, antigen, T-cell; signal transduction; T lymphocytes IntroductionThe physiological process of T-cell activation can be divided into a series of temporal stages consisting of initial adhesion, initial signaling (formation of the contact cap), and sustained signaling (Bromley et al., 2001). During these stages, two independent signals are required for the enactment of full T-cell activation: (1) specific interaction of a T-cell receptor (TCR) with a cognate peptide/MHC on APCs, and (2) the ligation of surface co-stimulatory molecules with specific ligands on APCs. Among the known costimulatory molecules, CD28 launches the most effective activation of T cells (Alegre et al., 2001;. However, recent reports have suggested that many other candidates, most of which reside in the lipid raft, induce T-cell activation as potently as CD28 does (Denning et al., 1988;Ledbetter et al., 1988;Green et al., 1994;Tai et al., 1996;Yashiro-Ohtani et al., 2000;Stillwell and Bierer, 2001).The lipid raft is a unique membrane microdomain that is enriched with specific types of lipids and cholesterol and is associated with many key molecules involved in TCR signaling. Upon engagement of cognate ligands (peptide/MHC), TCRs are recruited toward the raft along with a series of tyrosine-phosphorylated signaling molecules (Moran and Miceli, 1998;Xavier et al., 1998;Janes et al., 1999). The lipid raft thus serves as a stage for protein-protein interactions among many surface molecules, thereby instigating a series of signaling cascades following TCR engagement (Cherukuri et al., 2001).CD99, a monomeric 32-kDa transmembrane glycoprotein, is the product of mic2 and lacks significant homology to any functional or structural domains of known proteins (Schenkel et al., 2002). Ligation of CD99 with anti-CD99 mAb induces homotypic aggregation and apoptosis of thymocytes (Bernard et al., 1997) as well as up-regulation of cell-surface proteins, such as TCR and MHC classes I and II . A recent report suggested that reorganization of the cytoskeleton is involved in the function of CD99 (Cerisano et al., 2004).In this study, we explored the possible role and mechanism of CD99 as a co-stimulatory molecule in T-cell activation. CD99 engagement leads to the CD99 activates T cells via a costimulatory function that promotes raft association of TCR comp...

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“…The crucial biologic processes involving CD99 include lymphocyte development, cell adhesion and monocyte diapedesis, and expression of TCR, MHC class I and II as well as of some adhesion molecules (i.e., ELAM-1, VCAM-1, ICAM-1) by mobilization of these molecules from the Golgi to the plasma membrane (7)(8)(9)(10)(11)(12)(13)(14). In pathology, CD99 is found on the cell surface of EWS, acute lymphoblastic leukemia, thymic tumors, some spindle cell tumors (e.g., synovial sarcoma), hemangiopericytoma, meningioma, and malignant glioma, in which it confers high invasiveness and low survival rates (13,(15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

CD99 Triggering in Ewing Sarcoma Delivers a Lethal Signal through p53 Pathway Reactivation and Cooperates with Doxorubicin

Guerzoni

Fiori²,

Terracciano

et al. 2015

Clinical Cancer Research

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Purpose: The paucity of new drugs for the treatment of Ewing sarcoma (EWS) limits the cure of these patients. CD99 has a strong membranous expression in EWS cells and, being also necessary for tumor survival, is a suitable target to aim at. In this article, we described a novel human monospecific bivalent single-chain fragment variable diabody (dAbd C7) directed against CD99 of potential clinical application.Experimental Design: In vitro and in vivo evaluation of cell death and of the molecular mechanisms triggered by anti-CD99 agents were performed alone or in combination with doxorubicin to demonstrate efficacy and selectivity of the new dAbd C7.Results: The dAbd C7 induced rapid and massive EWS cell death through Mdm2 degradation and p53 reactivation. Mdm2 overexpression as well as silencing of p53 in p53wt EWS cells decreased CD99-induced EWS cell death, whereas treatment with nutlin-3 enhanced it. Furthermore, cell death was associated with induction of p21, bax, and mitochondrial depolarization together with substantial inhibition of tumor cell proliferation. Combined treatment of anti-CD99 dAbd C7 with doxorubicin was additive both in vitro and in vivo against EWS xenografts. Normal mesenchymal stem cells showed no p53 activation and were resistant to cell death, unless transformed by EWS-FLI, the oncogenic driver of EWS.Conclusions: These results indicate that dAbd C7 is a suitable candidate tool to target CD99 in patients with EWS able to spare normal stem cells from death as it needs an aberrant genetic context for the efficient delivery of CD99-triggered cell death.

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Engagement of CD99 triggers the exocytic transport of ganglioside GM1 and the reorganization of actin cytoskeleton

Cited by 21 publications

References 31 publications

Molecular mechanisms of CD99-induced caspase-independent cell death and cell–cell adhesion in Ewing's sarcoma cells: actin and zyxin as key intracellular mediators

Molecular mechanisms of CD99-induced caspase-independent cell death and cell–cell adhesion in Ewing's sarcoma cells: actin and zyxin as key intracellular mediators

CD99 activates T cells via a costimulatory function that promotes raft association of TCR complex and tyrosine phosphorylation of TCR ζ

CD99 Triggering in Ewing Sarcoma Delivers a Lethal Signal through p53 Pathway Reactivation and Cooperates with Doxorubicin

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