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Daina Lim, Yuning Lu, Christopher E Rudd
While the cytoskeletal protein talin binds to the β-chain of LFA-1, the immune cell adaptor SKAP1 (SKAP-55) binds to the α-chain of the same integrin via RapL. Whereas calpain protease cleavage of talin is important for LFA-1 activation, it has been unclear whether SKAP1 can alter the function of talin or its associated adaptor RIAM in T-cells. In this paper, we report that Skap1-/- T-cells showed a reduction in the translocation of talin and RIAM to the contact interface of T-cells with antigenic beads or dendritic cells (DCs) presenting OVA peptide to OT-1 T-cells...
April 2016: Immunology Letters
Yanbo Zhang, Hongyan Wang
Integrins not only mediate cell-cell and cell-extracellular matrix adhesion, but also affect the multitude of signal transduction cascades in control of cell survival, proliferation, differentiation and organ development. Mutations in integrins or the major effectors of integrin signalling pathways cause defective organ development, immunodeficiency, cancer or autoimmune disease. Understanding of the signalling events that drive integrin activation and signalling is therefore crucial to uncover the molecular mechanisms of these diseases...
April 2012: Immunology
Monika Raab, Xin Smith, Yves Matthess, Klaus Strebhardt, Christopher E Rudd
Although essential for T cell function, the identity of the T cell receptor (TCR) "inside-out" pathway for the activation of lymphocyte function-associated antigen 1 (LFA-1) is unclear. SKAP1 (SKAP-55) is the upstream regulator needed for TCR-induced RapL-Rap1 complex formation and LFA-1 activation. In this paper, we show that SKAP1 is needed for RapL binding to membranes in a manner dependent on the PH domain of SKAP1 and the PI3K pathway. A SKAP1 PH domain-inactivating mutation (i.e. R131M) markedly impaired RapL translocation to membranes for Rap1 and LFA-1 binding and the up-regulation of LFA-1-intercellular adhesion molecule 1 (ICAM-1) binding...
August 26, 2011: Journal of Biological Chemistry
Irene M Patzak, Sebastian Königsberger, Akira Suzuki, Tak W Mak, Friedemann Kiefer
The hematopoietic progenitor kinase 1 (HPK1) signals into MAPK and NFκB pathways downstream of immunoreceptors, but enigmatically is a negative regulator of leukocytes. Here, we report a novel role for HPK1 in regulating the activation of the adhesion molecule leukocyte function-associated antigen-1 (LFA-1). Upon TCR stimulation, mediated by binding of adhesion and degranulation promoting adaptor protein (ADAP) to SLP-76, a ternary complex composed of ADAP/55-kDa src kinase associated phosphoprotein (SKAP-55) and RIAM translocates to the membrane and causes membrane recruitment of the active small GTPase Ras-related protein 1 (Rap1)...
November 2010: European Journal of Immunology
Monika Raab, Hongyan Wang, Yuning Lu, Xin Smith, Zhonglin Wu, Klaus Strebhardt, John E Ladbury, Christopher E Rudd
Although essential for T cell function, the identity of the T cell receptor "inside-out" pathway for lymphocyte function-associated antigen 1 (LFA-1) adhesion has proved elusive. Here, we define the "inside-out" pathway mediated by N-terminal SKAP1 (SKAP-55) domain binding to the C-terminal SARAH domain of RapL. TcR induced Rap1-RapL complex formation and LFA-1 binding failed to occur in Skap1(-/-) primary T cells. SKAP1 generated a SKAP1-RapL-Rap1 complex that bound to LFA-1, whereas a RapL mutation (L224A) that abrogated SKAP1 binding without affecting MST1 disrupted component colocalization in vesicles as well as T cell-dendritic cell (DC) conjugation...
April 23, 2010: Immunity
Hongyan Wang, Yuning Lu, Christopher E Rudd
Immune adaptors SLP-76, ADAP and SKAP1 (SKAP-55) play central roles in anti-CD3 induced 'inside-out' signalling for LFA-1 activation and ICAM-1 adhesion. However, it has been unclear whether SKAP1 is also required for chemokine-induced T-cell motility. In this study, we found that SDF-1 and CCL21 induced similar motility in SKAP1 deficient (SKAP1-/-) and wild type (SKAP1+/+) resting, primary T-cells. In addition, the speed (i.e. 13 microM/min), tracking distance (i.e. length) and displacement values (i.e. direct distance between the start and the end positions of cell movement) in response to SDF1 were similar for SKAP1-/- and SKAP1+/+ primary, activated T-cells...
February 16, 2010: Immunology Letters
Hongyan Wang, Christopher E Rudd
Integrin adhesion is essential for aspects of immune function, including antigen presentation and migration in lymph nodes, germinal centers and sites of inflammation. Antigen receptors on B and T cells generate 'inside-out' signals for increased integrin clustering and adhesion. Although upstream components of B-cell-receptor or T-cell-receptor signaling are needed, the identity of key downstream effectors that mediate integrin adhesion is only just emerging. New candidates include immune-cell-specific adaptor proteins ADAP, SKAP-55 and SKAP-55-related (SKAP-55R)...
October 2008: Trends in Cell Biology
Helga Schneider, Hongyan Wang, Monika Raab, Elke Valk, Xin Smith, Matt Lovatt, Zhonglin Wu, Braudel Maqueira-Iglesias, Klaus Strebhardt, Christopher E Rudd
While the adaptor SKAP-55 mediates LFA-1 adhesion on T-cells, it is not known whether the adaptor regulates other aspects of signaling. SKAP-55 could potentially act as a node to coordinate the modulation of adhesion with downstream signaling. In this regard, the GTPase p21(ras) and the extracellular signal-regulated kinase (ERK) pathway play central roles in T-cell function. In this study, we report that SKAP-55 has opposing effects on adhesion and the activation of the p21(ras) -ERK pathway in T-cells. SKAP-55 deficient primary T-cells showed a defect in LFA-1 adhesion concurrent with the hyper-activation of the ERK pathway relative to wild-type cells...
March 5, 2008: PloS One
Hongyan Wang, Hebin Liu, Yuning Lu, Matt Lovatt, Bin Wei, Christopher E Rudd
The ADAP-SKAP-55 module regulates T-cell receptor (TCR)-induced integrin clustering and adhesion in T cells. However, it has been unclear whether ADAP and/or SKAP-55 is an effector of the response. ADAP controls SKAP-55 expression such that ADAP(-/-) T cells are also deficient in SKAP-55 expression. In this study, we report the phenotype of the SKAP-55-deficient mouse. SKAP-55(-/-) T cells retain ADAP expression yet show defects in beta1 and beta2 integrin adhesion, leukocyte function-associated antigen 1 (LFA-1) clustering, production of the cytokines interleukin-2 and gamma interferon, and proliferation...
October 2007: Molecular and Cellular Biology
Adam Mor, Michael L Dustin, Mark R Philips
Leukocyte-function-associated antigen-1 (LFA-1) is an integrin that is critical for T-cell adhesion and immunologic responses. As a transmembrane receptor and adhesion molecule, LFA-1 signals bidirectionally, whereby information about extracellular ligands is passed outside-in while cellular activation is transmitted inside-out to the adhesive ectodomain. Here, we review the role of small guanosine triphosphatases (GTPases) in LFA-1 signaling. Rap1, a Ras-related GTPase, appears to be central to LFA-1 function...
August 2007: Immunological Reviews
Gaël Ménasché, Stefanie Kliche, Emily J H Chen, Theresia E B Stradal, Burkhart Schraven, Gary Koretzky
One outcome of T-cell receptor (TCR) signaling is increased affinity and avidity of integrins for their ligands. This occurs through a process known as inside-out signaling, which has been shown to require several molecular components including the adapter proteins ADAP (adhesion and degranulation-promoting adapter protein) and SKAP-55 (55-kDa src kinase-associated phosphoprotein) and the small GTPase Rap1. Herein, we provide evidence linking ADAP and SKAP-55 to RIAM, a recently described adapter protein that binds selectively to active Rap1...
June 2007: Molecular and Cellular Biology
Jonathan S Duke-Cohan, Hyun Kang, Hebin Liu, Christopher E Rudd
The immune cell adaptor adhesion and degranulation promoting adaptor protein (ADAP) and its binding to T-cell adaptor Src kinase-associated protein of 55 kDa (SKAP-55) play a key role in the modulation of T-cell adhesion. While primary binding occurs via SKAP-55 SH3 domain binding to a proline-rich region in ADAP, a second interaction occurs between the ADAP C-terminal SH3 domain (ADAP-SH3c) and a non-canonical RKXXY294XXY297 motif in SKAP-55. Increasing numbers of non-canonical SH3 domain binding motifs have been identified in a number of biological systems...
May 12, 2006: Journal of Biological Chemistry
Eun-Kyeong Jo, Hongyan Wang, Christopher E Rudd
Lymphocyte function-associated antigen (LFA)-1 clustering, which is needed for high avidity binding to intercellular adhesion molecule (ICAM)-1 and -2, regulates T cell motility and T cell-antigen-presenting cell (APC) conjugation. In this study, down-regulation of SKAP-55 by small interfering RNAs (siRNAs) identified an essential role for this adaptor molecule in the T cell receptor (TCR)-mediated "inside-out signaling" that is needed for LFA-1 clustering and T cell-APC conjugation. In contrast, down-regulation of SKAP-55 had no effect on TCR-CD3 clustering...
June 6, 2005: Journal of Experimental Medicine
Luca Simeoni, Stefanie Kliche, Jonathan Lindquist, Burkhart Schraven
By mediating non-covalent protein-protein interactions, adaptors organize and assemble the multimolecular signalling complexes that coordinate intracellular programs leading to the activation and differentiation of lymphocytes. The co-ordinated interaction between adaptor and effector molecules is required for the propagation and dynamic modification of externally applied signals. Recent advances have been made regarding our understanding of how adaptors regulate signalling within lymphocytes. An unexpected function has been revealed for the well-known adaptor protein LAT in pre-B-cell receptor signalling...
June 2004: Current Opinion in Immunology
Nancy Hogg, Melanie Laschinger, Katherine Giles, Alison McDowall
T cells use integrins in essentially all of their functions. They use integrins to migrate in and out of lymph nodes and, following infection, to migrate into other tissues. At the beginning of an immune response, integrins also participate in the immunological synapse formed between T cells and antigen-presenting cells. Because the ligands for integrins are widely expressed, integrin activity on T cells must be tightly controlled. Integrins become active following signalling through other membrane receptors, which cause both affinity alteration and an increase in integrin clustering...
December 1, 2003: Journal of Cell Science
Christopher E Rudd, Hongyan Wang
Recent advances have been made in understanding the basis of T-cell signaling with the identification of hematopoeitic-specific adaptor proteins, or molecular scaffolds that facilitate protein complex formation and the integration of signals from the surface of T cells. Their potential relevance as targets in the modulation of transplantation relates to their immune-cell-specific expression and their ability to integrate signals needed for T-cell/APC conjugate formation, cytokine production and the clonal expansion of T cells...
October 2003: American Journal of Transplantation
Hongyan Wang, Eun-Yi Moon, Abdallah Azouz, Xiang Wu, Andrew Smith, Helga Schneider, Nancy Hogg, Christopher E Rudd
Src kinase-associated phosphoprotein of 55 kDa (SKAP-55; encoded by SCAP1) is a T cell adaptor protein of unknown function that contains a pleckstrin homology and an SH3 domain. Here we show that SKAP-55 regulates integrin-mediated adhesion and conjugate formation between T cells and antigen-presenting cells (APCs). SKAP-55 enhances adhesion to fibronectin and intercellular adhesion molecule-1 (ICAM-1), colocalizes with actin at the T cell-APC synapse and promotes the clustering of lymphocyte-associated antigen-1 (LFA-1)...
April 2003: Nature Immunology
J S Kennedy, M Raab, C E Rudd
Of the past several years progress in understanding TCR signal transduction has led to the discovery of new kinases, adapter molecules and multiple signaling pathways. The study of molecules such as LAT, SLP-76, FYB, SKAP-55 and VAV have revealed multiple mechanisms with which to control the activation of downstream signaling pathways through RAS, PLC gamma-1 and ERK/MAPK. Signaling through SLP-76 can play a role in TCR-induced cytoskeleton changes through activation of effector molecules in the RAC/RHO-family of GTPases...
November 1999: Cell Calcium
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