title: Inhibition of the kinase Csk in thymocytes reveals a requirement for actin remodeling in the initiation of full TCR signaling.
abstract: Signaling via the T cell antigen receptor (TCR) is initiated by Src-family kinases (SFKs). To understand how the kinase Csk, a negative regulator of SFKs, controls the basal state and the initiation of TCR signaling, we generated mice that express a Csk variant sensitive to an analog of the common kinase inhibitor PP1 (Csk(AS)). Inhibition of Csk(AS) in thymocytes, without engagement of the TCR, induced potent activation of SFKs and proximal TCR signaling up to phospholipase C-γ1 (PLC-γ1). Unexpectedly, increases in inositol phosphates, intracellular calcium and phosphorylation of the kinase Erk were impaired. Altering the actin cytoskeleton pharmacologically or providing costimulation via CD28 'rescued' those defects. Thus, Csk has a critical role in preventing TCR signaling. However, our studies also revealed a requirement for actin remodeling, initiated by costimulation, for full TCR signaling.
authors: Rosalind Russell-Ephraim P. Engleman Medical Research Center for Arthritis, Division of Rheumatology, Department of Medicine, University of California, San Francisco, California, USA.
authors: Ying Xim
authors: YX
authors: Tan
authors: Rosalind Russell-Ephraim P. Engleman Medical Research Center for Arthritis, Division of Rheumatology, Department of Medicine, University of California, San Francisco, California, USA.
authors: Boryana N
authors: BN
authors: Manz
authors: Rosalind Russell-Ephraim P. Engleman Medical Research Center for Arthritis, Division of Rheumatology, Department of Medicine, University of California, San Francisco, California, USA.
authors: Tanya S
authors: TS
authors: Freedman
authors: Department of Chemistry, University of Southern California, California, USA.
authors: Chao
authors: C
authors: Zhang
authors: 1] Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors: Kevan M
authors: KM
authors: Shokat
authors: 1] Rosalind Russell-Ephraim P. Engleman Medical Research Center for Arthritis, Division of Rheumatology, Department of Medicine, University of California, San Francisco, California, USA. [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA. [3] Department of Microbiology and Immunology, University of California, San Francisco, California, USA.
authors: Arthur
authors: A
authors: Weiss
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D018106:CD28 Antigens / Q000276:immunology; D000081247:CSK Tyrosine-Protein Kinase; D002478:Cells, Cultured; D015638:Cytochalasin D / Q000008:administration & dosage; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism*; D058105:Polymerization / Q000187:drug effects; D015202:Protein Engineering; D011720:Pyrazoles / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D060168:Thymocytes / Q000187:drug effects / Q000276:immunology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; D000199:Actins; D018106:CD28 Antigens; D050505:Mutant Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D011948:Receptors, Antigen, T-Cell; D015638:Cytochalasin D; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases