T Cell Receptor for Antigen Induces Linker for Activation of T Cell-dependent Activation of a Negative Signaling Complex Involving Dok-2, SHIP-1, and Grb-2

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2006 Oct 18

PMID 17043143

Citations 51

Authors

Shen Dong

Beatrice Corre

Eliane Foulon

Evelyne Dufour

Andre Veillette

Oreste Acuto

Frederique Michel

Affiliations

Soon will be listed here.

Abstract

Adaptor proteins positively or negatively regulate the T cell receptor for antigen (TCR) signaling cascade. We report that after TCR stimulation, the inhibitory adaptor downstream of kinase (Dok)-2 and its homologue Dok-1 are involved in a multimolecular complex including the lipid phosphatase Src homology 2 domain-containing inositol polyphosphate 5'-phosphatase (SHIP)-1 and Grb-2 which interacts with the membrane signaling scaffold linker for activation of T cells (LAT). Knockdown of LAT and SHIP-1 expression indicated that SHIP-1 favored recruitment of Dok-2 to LAT. Knockdown of Dok-2 and Dok-1 revealed their negative control on Akt and, unexpectedly, on Zap-70 activation. Our findings support the view that Dok-1 and -2 are critical elements of a LAT-dependent negative feedback loop that attenuates early TCR signal. Dok-1 and -2 may therefore exert a critical role in shaping the immune response and as gatekeepers for T cell tolerance.

Citing Articles

Imaging of biphasic signalosomes constructed by checkpoint receptor 2B4 in conventional and chimeric antigen receptor-T cells.

Matsushima R, Wakamatsu E, Machiyama H, Nishi W, Yoshida Y, Nishikawa T iScience. 2025; 28(1):111669.

PMID: 39886466 PMC: 11780131. DOI: 10.1016/j.isci.2024.111669.

SHIP-1 regulates the differentiation and function of Tregs via inhibiting mTORC1 activity.

Du Z, Wang J, Liu Q, Yang D, Sun X, Huang L Cell Mol Life Sci. 2024; 82(1):10.

PMID: 39709321 PMC: 11663208. DOI: 10.1007/s00018-024-05470-2.

DOK1 and DOK2 regulate CD8 T cell signaling and memory formation without affecting tumor cell killing.

Laletin V, Bernard P, Montersino C, Yamanashi Y, Olive D, Castellano R Sci Rep. 2024; 14(1):15053.

PMID: 38956389 PMC: 11220026. DOI: 10.1038/s41598-024-66075-0.

Immunotherapeutic implications of negative regulation by protein tyrosine phosphatases in T cells: the emerging cases of PTP1B and TCPTP.

Perez-Quintero L, Abidin B, Tremblay M Front Med (Lausanne). 2024; 11:1364778.

PMID: 38707187 PMC: 11066278. DOI: 10.3389/fmed.2024.1364778.

Immune Checkpoint Receptors Signaling in T Cells.

Baldanzi G Int J Mol Sci. 2022; 23(7).

PMID: 35408889 PMC: 8999077. DOI: 10.3390/ijms23073529.

References

Roose J, Diehn M, Tomlinson M, Lin J, Alizadeh A, Botstein D . T cell receptor-independent basal signaling via Erk and Abl kinases suppresses RAG gene expression. PLoS Biol. 2003; 1(2):E53. PMC: 261890. DOI: 10.1371/journal.pbio.0000053. View

Horejsi V, Zhang W, Schraven B . Transmembrane adaptor proteins: organizers of immunoreceptor signalling. Nat Rev Immunol. 2004; 4(8):603-16. DOI: 10.1038/nri1414. View

Duan L, Reddi A, Ghosh A, Dimri M, Band H . The Cbl family and other ubiquitin ligases: destructive forces in control of antigen receptor signaling. Immunity. 2004; 21(1):7-17. DOI: 10.1016/j.immuni.2004.06.012. View

Malbec O, Malissen M, Isnardi I, Lesourne R, Mura A, Fridman W . Linker for activation of T cells integrates positive and negative signaling in mast cells. J Immunol. 2004; 173(8):5086-94. DOI: 10.4049/jimmunol.173.8.5086. View

Horn S, Endl E, Fehse B, Weck M, Mayr G, Jucker M . Restoration of SHIP activity in a human leukemia cell line downregulates constitutively activated phosphatidylinositol 3-kinase/Akt/GSK-3beta signaling and leads to an increased transit time through the G1 phase of the cell cycle. Leukemia. 2004; 18(11):1839-49. DOI: 10.1038/sj.leu.2403529. View

Damen J, Liu L, Rosten P, Humphries R, Jefferson A, MAJERUS P . The 145-kDa protein induced to associate with Shc by multiple cytokines is an inositol tetraphosphate and phosphatidylinositol 3,4,5-triphosphate 5-phosphatase. Proc Natl Acad Sci U S A. 1996; 93(4):1689-93. PMC: 40003. DOI: 10.1073/pnas.93.4.1689. View

Carpino N, Wisniewski D, Strife A, Marshak D, Kobayashi R, Stillman B . p62(dok): a constitutively tyrosine-phosphorylated, GAP-associated protein in chronic myelogenous leukemia progenitor cells. Cell. 1997; 88(2):197-204. DOI: 10.1016/s0092-8674(00)81840-1. View

Yamanashi Y, Baltimore D . Identification of the Abl- and rasGAP-associated 62 kDa protein as a docking protein, Dok. Cell. 1997; 88(2):205-11. DOI: 10.1016/s0092-8674(00)81841-3. View

Di Cristofano A, Carpino N, Dunant N, Friedland G, Kobayashi R, Strife A . Molecular cloning and characterization of p56dok-2 defines a new family of RasGAP-binding proteins. J Biol Chem. 1998; 273(9):4827-30. DOI: 10.1074/jbc.273.9.4827. View

10.

Jones N, Dumont D . The Tek/Tie2 receptor signals through a novel Dok-related docking protein, Dok-R. Oncogene. 1998; 17(9):1097-108. DOI: 10.1038/sj.onc.1202115. View

11.

Finco T, Kadlecek T, Zhang W, Samelson L, Weiss A . LAT is required for TCR-mediated activation of PLCgamma1 and the Ras pathway. Immunity. 1998; 9(5):617-26. DOI: 10.1016/s1074-7613(00)80659-7. View

12.

Di Bartolo V, Mege D, Germain V, Pelosi M, Dufour E, Michel F . Tyrosine 319, a newly identified phosphorylation site of ZAP-70, plays a critical role in T cell antigen receptor signaling. J Biol Chem. 1999; 274(10):6285-94. DOI: 10.1074/jbc.274.10.6285. View

13.

Liu Q, Sasaki T, Kozieradzki I, Wakeham A, Itie A, Dumont D . SHIP is a negative regulator of growth factor receptor-mediated PKB/Akt activation and myeloid cell survival. Genes Dev. 1999; 13(7):786-91. PMC: 316591. DOI: 10.1101/gad.13.7.786. View

14.

Yamanashi Y, Tamura T, Kanamori T, Yamane H, Nariuchi H, Yamamoto T . Role of the rasGAP-associated docking protein p62(dok) in negative regulation of B cell receptor-mediated signaling. Genes Dev. 2000; 14(1):11-6. PMC: 316343. View

15.

LeMay S, Davidson D, Latour S, Veillette A . Dok-3, a novel adapter molecule involved in the negative regulation of immunoreceptor signaling. Mol Cell Biol. 2000; 20(8):2743-54. PMC: 85490. DOI: 10.1128/MCB.20.8.2743-2754.2000. View

16.

Tamir I, Stolpa J, Helgason C, Nakamura K, Bruhns P, Daeron M . The RasGAP-binding protein p62dok is a mediator of inhibitory FcgammaRIIB signals in B cells. Immunity. 2001; 12(3):347-58. DOI: 10.1016/s1074-7613(00)80187-9. View

17.

Nemorin J, Laporte P, Berube G, Duplay P . p62dok negatively regulates CD2 signaling in Jurkat cells. J Immunol. 2001; 166(7):4408-15. DOI: 10.4049/jimmunol.166.7.4408. View

18.

Latour S, Gish G, Helgason C, Humphries R, Pawson T, Veillette A . Regulation of SLAM-mediated signal transduction by SAP, the X-linked lymphoproliferative gene product. Nat Immunol. 2001; 2(8):681-90. DOI: 10.1038/90615. View

19.

Di Cristofano A, Niki M, Zhao M, Karnell F, Clarkson B, Pear W . p62(dok), a negative regulator of Ras and mitogen-activated protein kinase (MAPK) activity, opposes leukemogenesis by p210(bcr-abl). J Exp Med. 2001; 194(3):275-84. PMC: 2193466. DOI: 10.1084/jem.194.3.275. View

20.

Wick M, Dong L, Hu D, Langlais P, Liu F . Insulin receptor-mediated p62dok tyrosine phosphorylation at residues 362 and 398 plays distinct roles for binding GTPase-activating protein and Nck and is essential for inhibiting insulin-stimulated activation of Ras and Akt. J Biol Chem. 2001; 276(46):42843-50. DOI: 10.1074/jbc.M102116200. View