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Chunyang Li, Weiyun Li, Jun Xiao, Shaozhuo Jiao, Fei Teng, Shengjie Xue, Chi Zhang, Chun Sheng, Qibin Leng, Christopher E Rudd, Bin Wei, Hongyan Wang
PD-1 negatively regulates CD8(+) cytotoxic T lymphocytes (CTL) cytotoxicity and anti-tumor immunity. However, it is not fully understood how PD-1 expression on CD8(+) CTL is regulated during anti-tumor immunotherapy. In this study, we have identified that the ADAP-SKAP55 signaling module reduced CD8(+) CTL cytotoxicity and enhanced PD-1 expression in a Fyn-, Ca(2+)-, and NFATc1-dependent manner. In DC vaccine-based tumor prevention and therapeutic models, knockout of SKAP55 or ADAP showed a heightened protection from tumor formation or metastases in mice and reduced PD-1 expression in CD8(+) effector cells...
June 2015: EMBO Molecular Medicine
Claudio Agostinelli, Hasan Rizvi, Jennifer Paterson, Vishvesh Shende, Ayse U Akarca, Elena Agostini, Fabio Fuligni, Simona Righi, Sebastiano Spagnolo, Pier Paolo Piccaluga, Edward A Clark, Stefano A Pileri, Teresa Marafioti
Despite the immunologic functions of T-cell receptor signaling molecules being extensively investigated, their potential as immunohistochemical markers has been poorly explored. With this background, we evaluated the expression of 5 intracellular proteins-GADS, DOK2, SKAP55, ITK, and PKCα-involved in T-cell receptor signaling in normal and neoplastic hematologic tissue samples, using antibodies raised against fixation-resistant epitopes of the 5 molecules. All 5 antibodies were associated with normal T-cell differentiation...
October 2014: American Journal of Surgical Pathology
Michael J Ophir, Beiyun C Liu, Stephen C Bunnell
The T cell receptor (TCR) triggers the assembly of "SLP-76 microclusters," which mediate signals required for T cell activation. In addition to regulating integrin activation, we show that Src kinase-associated phosphoprotein of 55 kD (SKAP55) is required for microcluster persistence and movement, junctional stabilization, and integrin-independent adhesion via the TCR. These functions require the dimerization of SKAP55 and its interaction with the adaptor adhesion and degranulation-promoting adaptor protein (ADAP)...
December 23, 2013: Journal of Cell Biology
Jason S Mitchell, Brandon J Burbach, Rupa Srivastava, Brian T Fife, Yoji Shimizu
The Ag-specific interactions between T cells and dendritic cells progress through dynamic contact stages in vivo consisting of early long-term stable contacts and later confined, yet motile, short-lived contacts. The signaling pathways that control in vivo interaction dynamics between T cells and dendritic cells during priming remain undefined. Adhesion and degranulation promoting adapter protein (ADAP) is a multifunctional adapter that regulates "inside-out" signaling from the TCR to integrins. Using two-photon microscopy, we demonstrate that, in the absence of ADAP, CD4 T cells make fewer early-stage stable contacts with Ag-laden dendritic cells, and the interactions are characterized by brief repetitive contacts...
September 1, 2013: Journal of Immunology: Official Journal of the American Association of Immunologists
Rupa Srivastava, Brandon J Burbach, Jason S Mitchell, Antonio J Pagán, Yoji Shimizu
Adhesion and degranulation-promoting adapter protein (ADAP) is a multifunctional scaffold that regulates T cell receptor-mediated activation of integrins via association with the SKAP55 adapter and the NF-κB pathway through interactions with both the CARMA1 adapter and serine/threonine kinase transforming growth factor β-activated kinase 1 (TAK1). ADAP-deficient T cells exhibit impaired proliferation following T cell receptor stimulation, but the contribution of these distinct functions of ADAP to this defect is not known...
May 2012: Molecular and Cellular Biology
Stefanie Kliche, Tim Worbs, Xiaoqian Wang, Janine Degen, Irene Patzak, Bernhard Meineke, Mauro Togni, Markus Moser, Annegret Reinhold, Friedemann Kiefer, Christian Freund, Reinhold Förster, Burkhart Schraven
The β2-integrin lymphocyte function-associated antigen-1 (LFA-1) plays a crucial role within the immune system. It regulates the interaction between T cells and antigen-presenting cells and facilitates T-cell adhesion to the endothelium, a process that is important for lymphocyte extravasation and homing. Signals mediated via the T-cell receptor and the chemokine receptor CCR7 activate LFA-1 through processes known as inside-out signaling. The molecular mechanisms underlying inside-out signaling are not completely understood...
January 19, 2012: Blood
Brandon J Burbach, Rupa Srivastava, Melissa A Ingram, Jason S Mitchell, Yoji Shimizu
Adhesion and degranulation promoting adapter protein (ADAP) is a multifunctional hematopoietic adapter protein that regulates TCR-dependent increases in both integrin function and activation of the NF-κB transcription factor. Activation of integrin function requires both ADAP and the ADAP-associated adapter Src kinase-associated phosphoprotein of 55 kDa (SKAP55). In contrast, ADAP-mediated regulation of NF-κB involves distinct binding sites in ADAP that promote the inducible association of ADAP, but not SKAP55, with the CARMA1 adapter and the TAK1 kinase...
June 1, 2011: Journal of Immunology: Official Journal of the American Association of Immunologists
Sebastian Königsberger, Doris Peckl-Schmid, Nadja Zaborsky, Irene Patzak, Friedemann Kiefer, Gernot Achatz
BACKGROUND: Hematopoietic progenitor kinase 1 (HPK1) is a Ste20-related serine/threonine kinase activated by a range of environmental stimuli including genotoxic stress, growth factors, inflammatory cytokines and antigen receptor triggering. Being inducibly recruited to membrane-proximal signalling scaffolds to regulate NFAT, AP-1 and NFkappaB-mediated gene transcription in T-cells, the function of HPK1 in B-cells to date remains rather ill-defined. METHODOLOGY/PRINCIPAL FINDINGS: By using two loss of function models, we show that HPK1 displays a novel function in regulating B-cell integrin activity...
2010: PloS One
Jessica Horn, Xiaoqian Wang, Peter Reichardt, Theresia E Stradal, Nicole Warnecke, Luca Simeoni, Matthias Gunzer, Deborah Yablonski, Burkhart Schraven, Stefanie Kliche
Engagement of the TCR or of chemokine receptors such as CXCR4 induces adhesion and migration of T cells via so-called inside-out signaling pathways. The molecular processes underlying inside-out signaling events are as yet not completely understood. In this study, we show that TCR- and CXCR4-mediated activation of integrins critically depends on the membrane recruitment of the adhesion- and degranulation-promoting adapter protein (ADAP)/Src kinase-associated phosphoprotein of 55 kDa (SKAP55)/Rap1-interacting adapter protein (RIAM)/Rap1 module...
November 1, 2009: Journal of Immunology: Official Journal of the American Association of Immunologists
Annegret Reinhold, Sibylle Reimann, Dirk Reinhold, Burkhart Schraven, Mauro Togni
The cytosolic adaptor molecule SKAP-HOM, similar to the T cell-specific homologue SKAP55, interacts directly with ADAP, and both molecules are involved in inside-out signaling. Previous studies have shown that in the absence of SKAP-HOM, antigen receptor-triggered integrin-mediated adhesion is impaired severely in B cells but not in T cells. In addition, loss of SKAP-HOM results in a less severe clinical course of EAE. DCs are the most potent APCs and express SKAP-HOM. However, the role of SKAP-HOM in DCs remains unknown...
July 2009: Journal of Leukocyte Biology
Brandon J Burbach, Rupa Srivastava, Ricardo B Medeiros, William E O'Gorman, Erik J Peterson, Yoji Shimizu
Following TCR stimulation, T cells utilize the hematopoietic specific adhesion and degranulation-promoting adapter protein (ADAP) to control both integrin adhesive function and NF-kappaB transcription factor activation. We have investigated the molecular basis by which ADAP controls these events in primary murine ADAP(-/-) T cells. Naive DO11.10/ADAP(-/-) T cells show impaired adhesion to OVAp (OVA aa 323-339)-bearing APCs that is restored following reconstitution with wild-type ADAP. Mutational analysis demonstrates that the central proline-rich domain and the C-terminal domain of ADAP are required for rescue of T:APC conjugate formation...
October 1, 2008: Journal of Immunology: Official Journal of the American Association of Immunologists
Karena A Kosco, Fabio Cerignoli, Scott Williams, Robert T Abraham, Tomas Mustelin
Src kinase-associated phosphoprotein of 55 kDa (SKAP55) is an adapter protein with an N-terminal region, a pleckstrin homology domain, a linker with tyrosine phosphorylation sites, and a C-terminal Src homology 3 domain. We report that overexpression of SKAP55 disrupts signaling from the TCR to the Ras-Erk-AP-1 pathway and transcription of the IL-2 gene in primary human T cells and in Jurkat T leukemia cells. In contrast, moderate overexpression of SKAP55 increased TCR-dependent AP-1 transcriptional activity, suggesting that high-level SKAP55 overexpression interfered with the assembly of functional signaling complexes required for TCR coupling to the Ras pathway...
January 2008: Molecular Immunology
Kazuya Ikematsu, Ryouichi Tsuda, Shinichiro Tsuruya, Shin-ichi Kubo, Ichiro Nakasono
Toluene, an abused substance in Japan, is well known as a neurotoxic chemical and has been shown to have neurobehavioral and electrophysiological effects. We used a fluorescence differential display PCR technique to analyze the genes expressed in the brain by toluene inhalation. We found 20 genes that were differentially expressed by toluene exposure. We confirmed by re-amplified PCR, nucleotide sequence and quantitative real-time PCR that of the 20 cDNAs, only 10 showed reproducible expression patterns by toluene inhalation...
September 2007: Legal Medicine
Stefanie Kliche, Dennis Breitling, Mauro Togni, Rico Pusch, Katja Heuer, Xiaoqian Wang, Christian Freund, Ana Kasirer-Friede, Gael Menasche, Gary A Koretzky, Burkhart Schraven
Adhesion of T cells after stimulation of the T-cell receptor (TCR) is mediated via signaling processes that have collectively been termed inside-out signaling. The molecular basis for inside-out signaling is not yet completely understood. Here, we show that a signaling module comprising the cytosolic adapter proteins ADAP and SKAP55 is involved in TCR-mediated inside-out signaling and, moreover, that the interaction between ADAP and SKAP55 is mandatory for integrin activation. Disruption of the ADAP/SKAP55 module leads to displacement of the small GTPase Rap1 from the plasma membrane without influencing its GTPase activity...
October 2006: Molecular and Cellular Biology
Heidi L Cook, J Robin Lytle, Hannah E Mischo, Ming-Jie Li, John J Rossi, Daniel P Silva, Ronald C Desrosiers, Joan A Steitz
Seven small nuclear RNAs of the Sm class are encoded by Herpesvirus saimiri (HVS), a gamma Herpesvirus that causes aggressive T cell leukemias and lymphomas in New World primates and efficiently transforms T cells in vitro. The Herpesvirus saimiri U RNAs (HSURs) are the most abundant viral transcripts in HVS-transformed, latently infected T cells but are not required for viral replication or transformation in vitro. We have compared marmoset T cells transformed with wild-type or a mutant HVS lacking the most highly conserved HSURs, HSURs 1 and 2...
May 24, 2005: Current Biology: CB
Roland P Bourette, Julien Thérier, Guy Mouchiroud
The production, survival, and function of monocytes and macrophages are regulated by the macrophage colony-stimulating factor (M-CSF or CSF-1) through its tyrosine kinase receptor. M-CSF receptor activates multiple cytoplasmic pathways in which adaptor and scaffolding proteins play a central role. In this study, we showed that SKAP55-related (SKAP55R) adaptor protein is expressed in myeloid cells and macrophages and is rapidly and transiently tyrosine-phosphorylated in response to M-CSF. M-CSF induced SKAP55R association with other tyrosine-phosphorylated proteins and with actin...
August 2005: Cellular Signalling
Yanping Huang, Darrell D Norton, Patricia Precht, Jennifer L Martindale, Janis K Burkhardt, Ronald L Wange
ADAP (adhesion and degranulation-promoting adaptor protein) and SKAP55 (Src kinase-associated phosphoprotein of 55 kDa) are T cell adaptors that mediate inside-out signaling from the T cell antigen receptor to integrins, giving rise to increased integrin affinity/avidity and formation of the immunological synapse between the T cell and the antigen-presenting cell. These two proteins are tightly and constitutively associated with one another, and their ability to interact is required for inside-out signaling...
June 24, 2005: Journal of Biological Chemistry
Yasuyuki Fujii, Shunichi Wakahara, Toru Nakao, Toshifumi Hara, Hidenori Ohtake, Toshi Komurasaki, Kunihiro Kitamura, Akiko Tatsuno, Naruyoshi Fujiwara, Nobumichi Hozumi, Chisei Ra, Daisuke Kitamura, Ryo Goitsuka
MIST (mast cell immunoreceptor signal transducer; also termed Clnk) is an adaptor protein structurally related to SLP-76-family hematopoietic cell-specific adaptor proteins. We demonstrate here that two major MIST-associated phosphoproteins expressed in mast cell lines are SLAP-130 and SKAP55, adaptors known to interact with the Src-homology (SH) 2 domain of Src-family protein tyrosine kinases (PTKs). MIST directly associated with SLAP-130 via its SH2 domain, and collaboration of SLAP-130 with SKAP55 was required for the recruitment of MIST to Lyn...
April 10, 2003: FEBS Letters
Liangtang Wu, Zhenbao Yu, Shi-Hsiang Shen
T cell receptor (TCR) engagement triggers a series of events including protein tyrosine kinase activation, tyrosine phosphorylation of adapter proteins, and multiple protein-protein interactions. We observed that adapter protein SKAP55, the Src kinase-associated phosphoprotein, formed homodimers through its SH3 domain and SK region. SKAP55 as a substrate interacted with Fyn kinase in vivo. In Jurkat cells, interaction between SKAP55 and Fyn kinase depended on TCR activation. Stable overexpression of SKAP55 in Jurkat cells caused mitogen-activated protein kinase activation following TCR engagement...
October 25, 2002: Journal of Biological Chemistry
Liangtang Wu, Jun Fu, Shi-Hsiang Shen
CD45 plays a critical role in T-cell receptor (TCR)-mediated signaling. In a yeast two-hybrid screen, SKAP55, the Src kinase-associated phosphoprotein of unknown function, was found as a substrate which associated with CD45 in vivo. Mutational analysis demonstrated the pivotal role of Tyr-232 in SKAP55 in the association with CD45. In Jurkat cells, anti-CD3 antibody stimulation promoted SKAP55 tyrosine phosphorylation and translocation from the cytoplasm to the membrane. Overexpression of SKAP55 in these cells induced transcriptional activation of the IL-2 promoter, while mutant SKAP55-Y232F totally suppressed the promoter activity...
April 2002: Molecular and Cellular Biology
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