Inhibition of Zap-70 Kinase Activity via an Analog-sensitive Allele Blocks T Cell Receptor and Cd28 Superagonist Signaling
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چکیده
INHIBITION OF ZAP-70 KINASE ACTIVITY VIA AN ANALOG-SENSITIVE ALLELE BLOCKS T CELL RECEPTOR AND CD28 SUPERAGONIST SIGNALING Susan E. Levin, Chao Zhang, Theresa A. Kadlecek, Kevan M. Shokat, Arthur Weiss Biomedical Sciences Graduate Program, Departments of Medicine, and of Microbiology and Immunology, Rosalind Russell Medical Research Center for Arthritis, Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, CA, 94143 Running head: Inhibition of ZAP-70 Kinase Activity Address correspondence to: Arthur Weiss, MD, PhD, 513 Parnassus Avenue, Box 0795, San Francisco, CA 94143. Fax: 415-502-5081; Email: [email protected]
منابع مشابه
Inhibition of ZAP-70 Kinase Activity via an Analog-sensitive Allele Blocks T Cell Receptor and CD28 Superagonist Signaling*S⃞
ZAP-70 is a cytoplasmic protein tyrosine kinase that is required for T cell antigen receptor (TCR) signaling. Both mice and humans deficient in ZAP-70 fail to develop functional T cells, thus demonstrating its necessity for T cell development and function. There is currently no highly specific, cell-permeable, small molecule inhibitor for ZAP-70; therefore, we generated a mutant ZAP-70 allele t...
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CD28 costimulation amplifies TCR-dependent signaling in activated T cells, however, the biochemical mechanism(s) by which this occurs is not precisely understood. The small GTPase Rac-1 controls the catalytic activity of the mitogen-activated protein kinases (MAPKs) and cell cycle progression through G1. Rac-1 activation requires the phospho-tyrosine (p-Tyr)-dependent recruitment of the Vav GDP...
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T cell activation by antigens binding to the T cell receptor (TCR) must be properly regulated to ensure normal T cell development and effective immune responses to pathogens and transformed cells while avoiding autoimmunity. The Src family kinase Lck and the Syk family kinase ZAP-70 (ζ chain-associated protein kinase of 70 kD) are sequentially activated in response to TCR engagement and serve a...
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Expression of ZAP-70 is an important negative prognostic factor in chronic lymphocytic leukemia (CLL). This protein tyrosine kinase is a key mediator of T-cell receptor (TCR) signaling and is structurally homologous to Syk, which plays an analogous role in B-cell receptor (BCR) signaling. Recent studies indicate that ZAP-70 may participate in BCR signaling as well, but the mechanism of action i...
متن کاملStructural Basis for the Inhibition of Tyrosine Kinase Activity of ZAP-70
ZAP-70, a cytoplasmic tyrosine kinase required for T cell antigen receptor signaling, is controlled by a regulatory segment that includes a tandem SH2 unit responsible for binding to immunoreceptor tyrosine-based activation motifs (ITAMs). The crystal structure of autoinhibited ZAP-70 reveals that the inactive kinase domain adopts a conformation similar to that of cyclin-dependent kinases and S...
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تاریخ انتشار 2008