Inhibition of the Kinase Csk in Thymocytes Reveals a Requirement for Actin Remodeling in the Initiation of Full TCR Signaling

Overview

Journal Nat Immunol

Date 2013 Dec 10

PMID 24317039

Citations 52

Authors

Ying Xim Tan

Boryana N Manz

Tanya S Freedman

Chao Zhang

Kevan M Shokat

Arthur Weiss

Affiliations

Soon will be listed here.

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.

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References

Kawabuchi M, Satomi Y, Takao T, Shimonishi Y, Nada S, Nagai K . Transmembrane phosphoprotein Cbp regulates the activities of Src-family tyrosine kinases. Nature. 2000; 404(6781):999-1003. DOI: 10.1038/35010121. View

van Rheenen J, Song X, van Roosmalen W, Cammer M, Chen X, DesMarais V . EGF-induced PIP2 hydrolysis releases and activates cofilin locally in carcinoma cells. J Cell Biol. 2007; 179(6):1247-59. PMC: 2140025. DOI: 10.1083/jcb.200706206. View

Buhlmann J, Elkin S, Sharpe A . A role for the B7-1/B7-2:CD28/CTLA-4 pathway during negative selection. J Immunol. 2003; 170(11):5421-8. DOI: 10.4049/jimmunol.170.11.5421. View

Salazar-Fontana L, Barr V, Samelson L, Bierer B . CD28 engagement promotes actin polymerization through the activation of the small Rho GTPase Cdc42 in human T cells. J Immunol. 2003; 171(5):2225-32. DOI: 10.4049/jimmunol.171.5.2225. View

Blin G, Margeat E, Carvalho K, Royer C, Roy C, Picart C . Quantitative analysis of the binding of ezrin to large unilamellar vesicles containing phosphatidylinositol 4,5 bisphosphate. Biophys J. 2007; 94(3):1021-33. PMC: 2186265. DOI: 10.1529/biophysj.107.110213. View

Burkhardt J, Carrizosa E, Shaffer M . The actin cytoskeleton in T cell activation. Annu Rev Immunol. 2008; 26:233-59. DOI: 10.1146/annurev.immunol.26.021607.090347. View

Borriello F, Sethna M, Boyd S, Schweitzer A, Tivol E, Jacoby D . B7-1 and B7-2 have overlapping, critical roles in immunoglobulin class switching and germinal center formation. Immunity. 1997; 6(3):303-13. DOI: 10.1016/s1074-7613(00)80333-7. View

Nika K, Soldani C, Salek M, Paster W, Gray A, Etzensperger R . Constitutively active Lck kinase in T cells drives antigen receptor signal transduction. Immunity. 2010; 32(6):766-77. PMC: 2996607. DOI: 10.1016/j.immuni.2010.05.011. View

Boomer J, Green J . An enigmatic tail of CD28 signaling. Cold Spring Harb Perspect Biol. 2010; 2(8):a002436. PMC: 2908766. DOI: 10.1101/cshperspect.a002436. View

10.

Gross J, Callas E, Allison J . Identification and distribution of the costimulatory receptor CD28 in the mouse. J Immunol. 1992; 149(2):380-8. View

11.

Kusumi A, Nakada C, Ritchie K, Murase K, Suzuki K, Murakoshi H . Paradigm shift of the plasma membrane concept from the two-dimensional continuum fluid to the partitioned fluid: high-speed single-molecule tracking of membrane molecules. Annu Rev Biophys Biomol Struct. 2005; 34:351-78. DOI: 10.1146/annurev.biophys.34.040204.144637. View

12.

CHOW L, Fournel M, Davidson D, Veillette A . Negative regulation of T-cell receptor signalling by tyrosine protein kinase p50csk. Nature. 1993; 365(6442):156-60. DOI: 10.1038/365156a0. View

13.

Polic B, Kunkel D, Scheffold A, Rajewsky K . How alpha beta T cells deal with induced TCR alpha ablation. Proc Natl Acad Sci U S A. 2001; 98(15):8744-9. PMC: 37506. DOI: 10.1073/pnas.141218898. View

14.

Tischer B, von Einem J, Kaufer B, Osterrieder N . Two-step red-mediated recombination for versatile high-efficiency markerless DNA manipulation in Escherichia coli. Biotechniques. 2006; 40(2):191-7. DOI: 10.2144/000112096. View

15.

Imamoto A, Soriano P . Disruption of the csk gene, encoding a negative regulator of Src family tyrosine kinases, leads to neural tube defects and embryonic lethality in mice. Cell. 1993; 73(6):1117-24. DOI: 10.1016/0092-8674(93)90641-3. View

16.

Xu S, Huo J, Tan J, Lam K . Cbp deficiency alters Csk localization in lipid rafts but does not affect T-cell development. Mol Cell Biol. 2005; 25(19):8486-95. PMC: 1265734. DOI: 10.1128/MCB.25.19.8486-8495.2005. View

17.

van Oers N, Killeen N, Weiss A . ZAP-70 is constitutively associated with tyrosine-phosphorylated TCR zeta in murine thymocytes and lymph node T cells. Immunity. 1994; 1(8):675-85. DOI: 10.1016/1074-7613(94)90038-8. View

18.

Sligh Jr J, Ballantyne C, Rich S, Hawkins H, Smith C, Bradley A . Inflammatory and immune responses are impaired in mice deficient in intercellular adhesion molecule 1. Proc Natl Acad Sci U S A. 1993; 90(18):8529-33. PMC: 47390. DOI: 10.1073/pnas.90.18.8529. View

19.

Barker S, Kassel D, Weigl D, Huang X, Luther M, Knight W . Characterization of pp60c-src tyrosine kinase activities using a continuous assay: autoactivation of the enzyme is an intermolecular autophosphorylation process. Biochemistry. 1995; 34(45):14843-51. DOI: 10.1021/bi00045a027. View

20.

Smith-Garvin J, Koretzky G, Jordan M . T cell activation. Annu Rev Immunol. 2009; 27:591-619. PMC: 2740335. DOI: 10.1146/annurev.immunol.021908.132706. View