Focal Adhesion Kinase Negatively Regulates Lck Function Downstream of the T Cell Antigen Receptor

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2013 Nov 15

PMID 24227778

Citations 28

Authors

Nicole M Chapman

Sean F Connolly

Erin L Reinl

Jon C D Houtman

Affiliations

Soon will be listed here.

Abstract

Focal adhesion kinase (FAK) is a critical regulator of signal transduction in multiple cell types. Although this protein is activated upon TCR engagement, the cellular function that FAK plays in mature human T cells is unknown. By suppressing the function of FAK, we revealed that FAK inhibits TCR-mediated signaling by recruiting C-terminal Src kinase to the membrane and/or receptor complex following TCR activation. Thus, in the absence of FAK, the inhibitory phosphorylation of Lck and/or Fyn is impaired. Together, these data highlight a novel role for FAK as a negative regulator TCR function in human T cells. These results also suggest that changes in FAK expression could modulate sensitivity to TCR stimulation and contribute to the progression of T cell malignancies and autoimmune diseases.

Citing Articles

FDA-approved Abl/EGFR/PDGFR kinase inhibitors show potent efficacy against pandemic and seasonal influenza A virus infections of human lung explants.

Meineke R, Stelz S, Busch M, Werlein C, Kuhnel M, Jonigk D iScience. 2023; 26(4):106309.

PMID: 36968089 PMC: 10034449. DOI: 10.1016/j.isci.2023.106309.

Focal Adhesion-Related Signatures Predict the Treatment Efficacy of Chemotherapy and Prognosis in Patients with Gastric Cancer.

Tang X, Wu X, Guo T, Jia F, Hu Y, Xing X Front Oncol. 2022; 12:808817.

PMID: 35600404 PMC: 9115387. DOI: 10.3389/fonc.2022.808817.

T cell receptor (TCR) signaling in health and disease.

Shah K, Al-Haidari A, Sun J, Kazi J Signal Transduct Target Ther. 2021; 6(1):412.

PMID: 34897277 PMC: 8666445. DOI: 10.1038/s41392-021-00823-w.

A randomized phase 2 trial of idiotype vaccination and adoptive autologous T-cell transfer in patients with multiple myeloma.

Qazilbash M, Saini N, Cha S, Wang Z, Stadtmauer E, Baladandayuthapani V Blood. 2021; 139(9):1289-1301.

PMID: 34521108 PMC: 8900281. DOI: 10.1182/blood.2020008493.

ZINC40099027 Promotes Gastric Mucosal Repair in Ongoing Aspirin-Associated Gastric Injury by Activating Focal Adhesion Kinase.

Oncel S, Gupta R, Wang Q, Basson M Cells. 2021; 10(4).

PMID: 33920786 PMC: 8071155. DOI: 10.3390/cells10040908.

References

Collins M, Bartelt R, Houtman J . T cell receptor activation leads to two distinct phases of Pyk2 activation and actin cytoskeletal rearrangement in human T cells. Mol Immunol. 2010; 47(9):1665-74. DOI: 10.1016/j.molimm.2010.03.009. View

Songyang Z, Shoelson S, McGlade J, Olivier P, Pawson T, Bustelo X . Specific motifs recognized by the SH2 domains of Csk, 3BP2, fps/fes, GRB-2, HCP, SHC, Syk, and Vav. Mol Cell Biol. 1994; 14(4):2777-85. PMC: 358643. DOI: 10.1128/mcb.14.4.2777-2785.1994. View

Lee K, Holdorf A, Dustin M, Chan A, Allen P, Shaw A . T cell receptor signaling precedes immunological synapse formation. Science. 2002; 295(5559):1539-42. DOI: 10.1126/science.1067710. View

Berg N, Ostergaard H . T cell receptor engagement induces tyrosine phosphorylation of FAK and Pyk2 and their association with Lck. J Immunol. 1997; 159(4):1753-7. 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

Fukai I, Hussey R, Sunder-Plassmann R, Reinherz E . A critical role for p59(fyn) in CD2-based signal transduction. Eur J Immunol. 2000; 30(12):3507-15. DOI: 10.1002/1521-4141(2000012)30:12<3507::AID-IMMU3507>3.0.CO;2-O. View

Lahoute C, Herbin O, Mallat Z, Tedgui A . Adaptive immunity in atherosclerosis: mechanisms and future therapeutic targets. Nat Rev Cardiol. 2011; 8(6):348-58. DOI: 10.1038/nrcardio.2011.62. View

Sakaguchi S, Benham H, Cope A, Thomas R . T-cell receptor signaling and the pathogenesis of autoimmune arthritis: insights from mouse and man. Immunol Cell Biol. 2012; 90(3):277-87. DOI: 10.1038/icb.2012.4. View

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

10.

Roberts W, Ung E, Whalen P, Cooper B, Hulford C, Autry C . Antitumor activity and pharmacology of a selective focal adhesion kinase inhibitor, PF-562,271. Cancer Res. 2008; 68(6):1935-44. DOI: 10.1158/0008-5472.CAN-07-5155. View

11.

Tse K, Dang-Lawson M, Lee R, Vong D, Bulic A, Buckbinder L . B cell receptor-induced phosphorylation of Pyk2 and focal adhesion kinase involves integrins and the Rap GTPases and is required for B cell spreading. J Biol Chem. 2009; 284(34):22865-77. PMC: 2755694. DOI: 10.1074/jbc.M109.013169. View

12.

Dietz A, Bulur P, Emery R, Winters J, Epps D, Zubair A . A novel source of viable peripheral blood mononuclear cells from leukoreduction system chambers. Transfusion. 2006; 46(12):2083-9. DOI: 10.1111/j.1537-2995.2006.01033.x. View

13.

Schlaepfer D, Hanks S, Hunter T, van der Geer P . Integrin-mediated signal transduction linked to Ras pathway by GRB2 binding to focal adhesion kinase. Nature. 1994; 372(6508):786-91. DOI: 10.1038/372786a0. View

14.

Sieg D, Ilic D, Jones K, Damsky C, Hunter T, Schlaepfer D . Pyk2 and Src-family protein-tyrosine kinases compensate for the loss of FAK in fibronectin-stimulated signaling events but Pyk2 does not fully function to enhance FAK- cell migration. EMBO J. 1998; 17(20):5933-47. PMC: 1170921. DOI: 10.1093/emboj/17.20.5933. View

15.

Garron M, Arthos J, Guichou J, McNally J, Cicala C, Arold S . Structural basis for the interaction between focal adhesion kinase and CD4. J Mol Biol. 2007; 375(5):1320-8. DOI: 10.1016/j.jmb.2007.11.040. View

16.

Lloyd C, Hessel E . Functions of T cells in asthma: more than just T(H)2 cells. Nat Rev Immunol. 2010; 10(12):838-48. PMC: 3807783. DOI: 10.1038/nri2870. View

17.

Parsons S, Sharma R, Roccamatisi D, Zhang H, Petri B, Kubes P . Endothelial paxillin and focal adhesion kinase (FAK) play a critical role in neutrophil transmigration. Eur J Immunol. 2011; 42(2):436-46. DOI: 10.1002/eji.201041303. View

18.

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

19.

Bunnell S, Kapoor V, Trible R, Zhang W, Samelson L . Dynamic actin polymerization drives T cell receptor-induced spreading: a role for the signal transduction adaptor LAT. Immunity. 2001; 14(3):315-29. DOI: 10.1016/s1074-7613(01)00112-1. View

20.

Cahir McFarland E, Hurley T, Pingel J, Sefton B, Shaw A, Thomas M . Correlation between Src family member regulation by the protein-tyrosine-phosphatase CD45 and transmembrane signaling through the T-cell receptor. Proc Natl Acad Sci U S A. 1993; 90(4):1402-6. PMC: 45881. DOI: 10.1073/pnas.90.4.1402. View