Interaction of peptides derived from the Fas ligand with the Fyn‐SH3 domain

Hane, Michael; Lowin, Bente; Peitsch, Manuel C.; Becker, Karin; Tschopp, Jürg

doi:10.1016/0014-5793(95)01051-f

Cited by 53 publications

(43 citation statements)

References 20 publications

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“…These include the Src-like kinases Fyn, Lyn, and Fgr and the adaptor proteins Nck, Grb2 and PSTPIP. 28,[35][36][37][38][39] Of interest is the recently described interaction between Nck and FasL, as Nck likely links preformed and granule-stored FasL to WASP and the cytoskeleton. 38 In agreement with our observation that PMA-induced FasL degranulation was latrunculin B-sensitive it was found that the delivery of FasL to the immunological synapse was dependent on actin filament formation.…”

Section: Discussionmentioning

confidence: 99%

Distinct requirements for activation-induced cell surface expression of preformed Fas/CD95 ligand and cytolytic granule markers in T cells

et al. 2008

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Fas (CD95/Apo-1) ligand is a potent inducer of apoptosis and one of the major killing effector mechanisms of cytotoxic T cells. Thus, Fas ligand activity has to be tightly regulated, involving various transcriptional and post-transcriptional processes. For example, preformed Fas ligand is stored in secretory lysosomes of activated T cells, and rapidly released by degranulation upon reactivation. In this study, we analyzed the minimal requirements for activation-induced degranulation of Fas ligand. T cell receptor activation can be mimicked by calcium ionophore and phorbol ester. Unexpectedly, we found that stimulation with phorbol ester alone is sufficient to trigger Fas ligand release, whereas calcium ionophore is neither sufficient nor necessary. The relevance of this process was confirmed in primary CD4 þ and CD8 þ T cells and NK cells. Although the activation of protein kinase(s) was absolutely required for Fas ligand degranulation, protein kinase C or A were not involved. Previous reports have shown that preformed Fas ligand co-localizes with other markers of cytolytic granules. We found, however, that the activationinduced degranulation of Fas ligand has distinct requirements and involves different mechanisms than those of the granule markers CD63 and CD107a/Lamp-1. We conclude that activation-induced degranulation of Fas ligand in cytotoxic lymphocytes is differently regulated than other classical cytotoxic granule proteins.

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Section: Discussionmentioning

confidence: 99%

Distinct requirements for activation-induced cell surface expression of preformed Fas/CD95 ligand and cytolytic granule markers in T cells

et al. 2008

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“…Cellular proteins interacting with the intracellular FasL domain may also influence the capability of the ligand to induce apoptosis by Fas receptor activation, for example by preventing oligomerization of FasL. So far, the molecules that bind to the intracellular FasL domain and are responsible for such aspects of FasL biology have not been functionally characterized, although different proteins have been suggested as FasL-interacting proteins (28,29).…”

Section: Discussionmentioning

confidence: 99%

Binding of the Intracellular Fas Ligand (FasL) Domain to the Adaptor Protein PSTPIP Results in a Cytoplasmic Localization of FasL

Baum

Kirkin

Fernández

et al. 2005

Journal of Biological Chemistry

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The tumor necrosis factor family member Fas ligand (FasL) induces apoptosis in Fas receptor-expressing target cells and is an important cytotoxic effector molecule used by CTL-and NK-cells. In these hematopoietic cells, newly synthesized FasL is stored in specialized secretory lysosomes and only delivered to the cell surface upon activation and target cell recognition. FasL contains an 80-amino acid-long cytoplasmic tail, which includes a proline-rich domain as a bona fide Src homology 3 domain-binding site. This proline-rich domain has been implicated in FasL sorting to secretory lysosomes, and it may also be important for reverse signaling via FasL, which has been described to influence T-cell activation. Here we report the identification of the Src homology 3 domaincontaining adaptor protein PSTPIP as a FasL-interacting partner, which binds to the proline-rich domain. PSTPIP co-expression leads to an increased intracellular localization of Fas ligand, thereby regulating extracellular availability and cytotoxic activity of the molecule. In addition, we demonstrate recruitment of the tyrosine phosphatase PTP-PEST by PSTPIP into FasL⅐PSTPIP⅐PTP-PEST complexes which may contribute to FasL reverse signaling.Fas ligand (FasL 3 ; CD95/APO-1 ligand, CD178, TNFSF6) is a 281-amino acid (aa)-long type II transmembrane molecule belonging to the large TNF family of proteins that bind to and activate members of the TNF receptor family (1, 2). FasL and its corresponding receptor Fas (CD95/APO-1) both interact as oligomers (3), and the activated Fas receptor complex initiates a proapoptotic death signal in the receptorbearing cell (4, 5).Although mainly known for its death-promoting activity, FasL has also been studied in the context of further nonapoptotic functions (1, 2, 6). Such experiments are motivated by the special structure of this type II transmembrane protein. In addition to its hydrophobic transmembrane domain, which anchors the molecule within the plasma membrane, and to its extracellular ectodomain, responsible for binding to its receptor, the FasL protein possesses an 80-aa-long N-terminal intracellular part that is responsible for the transduction of (extracellular) signals into FasL-bearing cells and/or that may fulfill regulatory functions. Such a "reverse signaling" has been described in mouse T-cells, which display an altered proliferative behavior upon triggering of their FasL surface molecules (7-9). Results obtained with mouse Sertoli cells, in which FasL engagement leads to mitogen-activated protein kinase activation, as measured by an increase in Erk phosphorylation, also imply stimulatory FasL reverse signaling (10).The importance of the intracellular domain for FasL function and regulation is underlined by its high homology among different species (7,11,12). Several signaling motives within the FasL intracellular domain are highly conserved, including a tandem casein kinase I phosphorylation site (aa 17-21 (11)), a phosphorylatable tyrosine at position 7, a proline-rich region (aa 40 -70) with bona...

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“…After 1 year, it was found that peptides corresponding to the proline-rich region of the murine CD95L (aa 40-77) were able to selectively interact with the SH3 domains of the Src-related kinase p59 fyn(T) . 60 From this it was suggested that CD95L membrane expression is primarily regulated through an activation-independent SH3-mediated association with p59 fyn(T) . In 1996, Hachiya and co-workers deposited several protein fragments in the NCBI database, which were found to interact with CD95L in a yeast two-hybrid screen.…”

Section: Prd As a Protein-docking Site Of Cd95lmentioning

confidence: 99%

CD95 ligand - death factor and costimulatory molecule?

et al. 2003

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The CD95 ligand is involved as a death factor in the regulation of activation-induced cell death, establishment of immune privilege and tumor cell survival. In addition, CD95L may serve as a costimulatory molecule for T-cell activation. Alterations in expression or shedding of membrane and soluble CD95L are associated with numerous diseases, and underscore the pathophysiological relevance of the CD95/CD95L system. In most cases, the causal link between altered CD95L expression and pathophysiology is unknown. Given the potency of the molecule to regulate death and survival of many different cell types, the control of CD95L production, transport, storage, shedding and inactivation is of tremendous biological and clinical interest. This review summarizes the current knowledge, hypotheses and controversies about CD95L as a multifunctional ligand and receptor. It considers the different roles of membrane and soluble forms of CD95L and the complex networks of intracellular dynamics of protein trafficking, as well as the potential bidirectional signal transduction capacity of CD95L, with a focus on molecular interactions that have been worked out over the past years.

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Interaction of peptides derived from the Fas ligand with the Fyn‐SH3 domain

Cited by 53 publications

References 20 publications

Distinct requirements for activation-induced cell surface expression of preformed Fas/CD95 ligand and cytolytic granule markers in T cells

Distinct requirements for activation-induced cell surface expression of preformed Fas/CD95 ligand and cytolytic granule markers in T cells

Binding of the Intracellular Fas Ligand (FasL) Domain to the Adaptor Protein PSTPIP Results in a Cytoplasmic Localization of FasL

CD95 ligand - death factor and costimulatory molecule?

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