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Critical Reviews™ in Immunology
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Critical Reviews™ in Immunology

DOI: 10.1615/CritRevImmunol.2019030480
pages 59-81

TAOK3, a Regulator of LCK–SHP-1 Crosstalk during TCR Signaling

João V. S. Ormonde
Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California; Microbiome and Disease Tolerance Centre, and Department of Microbiology and Immunology, McGill University, Montréal, Quebec
Yan Nie
Department of Biochemistry, McGill University, Montréal, Quebec
Joaquin Madrenas
Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California; Microbiome and Disease Tolerance Centre, and Department of Microbiology and Immunology, McGill University, Montréal, Quebec


Signaling from the T cell receptor for antigen turns on the physiological response of a T cell. The canonical TCR signaling pathway relies on early activation of the Src kinase LCK. This step initiates a cascade of events that lead not only to the phenotypic changes that characterize effector T cells but also to the activation of negative regulatory mechanisms that stop early TCR signaling. These mechanisms ensure qualitative and quantitative fine-tuning of T cell activation. The tyrosine phosphatase SHP-1 is a key player in the downregulation of LCK activation. In this review, we focus on the crosstalk between LCK and SHP-1 and, based on recent data, we introduce the putative kinase TAOK3 as an important regulator of this crosstalk. Given the widespread expression of TAOK3 and SHP-1, we propose that the function of TAOK3 extends beyond T cells and may be fundamental in the regulation of early signaling from receptors that utilize Src kinases.


  1. Hirahara K, Nakayama T. CD4+ T-cell subsets in inflammatory diseases: beyond the Th1/Th2 paradigm. Int Immunol. 2016;28(4):163-71.

  2. Su X, Ditlev JA, Hui E, Xing W, Banjade S, Okrut J, King DS, Taunton J, Rosen MK, Vale RD. Phase separation of signaling molecules promotes T cell receptor signal transduction. Science. 2016;352(6285):595-9.

  3. Carbone CB, Kern N, Fernandes RA, Hui E, Su X, Garcia KC, Vale RD. In vitro reconstitution of T cell receptor- mediated segregation of the CD45 phosphatase. Proc Natl Acad Sci U S A. 2017;114(44):E9338-45.

  4. Courtney AH, Lo WL, Weiss A. TCR signaling: mechanisms of initiation and propagation. Trends Biochem Sci. 2018;43(2):108-23.

  5. Gaud G, Lesourne R, Love PE. Regulatory mechanisms in T cell receptor signalling. Nat Rev Immunol. 2018;18(8):485-97.

  6. Yang M, Chen T, Li X, Yu Z, Tang S, Wang C, Gu Y, Liu Y, Xu S, Li W, Zhang X, Wang J, Cao X. K33-linked polyubiquitination of Zap70 by Nrdp1 controls CD8(+) T cell activation. Nat Immunol. 2015;16(12):1253-62.

  7. Bouchet J, Del Rio-Iniguez I, Vazquez-Chavez E, Lasserre R, Aguera-Gonzalez S, Cuche C, Mccaffrey MW, Di Bartolo V, Alcover A. Rab11-FIP3 regulation of Lck endosomal Traffic controls TCR signal transduction. J Immunol. 2017;198(7):2967-78.

  8. Brownlie RJ, Zamoyska R. T cell receptor signalling networks: branched, diversified and bounded. Nat Rev Immunol. 2013;13(4):257-69.

  9. Cole DK, Pumphrey NJ, Boulter JM, Sami M, Bell JI, Gostick E, Price DA, Gao GF, Sewell AK, Jakobsen BK. Human TCR-binding affinity is governed by MHC class restriction. J Immunol. 2007;178(9):5727-34.

  10. Bridgeman JS, Sewell AK, Miles JJ, Price DA, Cole DK. Structural and biophysical determinants of alphabeta T-cell antigen recognition. Immunology. 2012;135(1):9-18.

  11. Cole DK, Miles KM, Madura F, Holland CJ, Schauenburg AJ, Godkin AJ, Bulek AM, Fuller A, Akpovwa HJ, Pymm PG, Liddy N, Sami M, Li Y, Rizkallah PJ, Jakobsen BK, Sewell AK. T-cell receptor (TCR)-peptide 22. specificity overrides affinity-enhancing TCR-major histocompatibility complex interactions. J Biol Chem. 2014;289(2):628-38.

  12. Gee MH, Sibener LV, Birnbaum ME, Jude KM, Yang X, Fernandes RA, Mendoza JL, Glassman CR, Garcia 23. KC. Stress-testing the relationship between T cell receptor/peptide-MHC affinity and cross-reactivity using peptide velcro. Proc Natl Acad Sci U S A. 2018;115(31): E7369-78.

  13. Ueno T, Tomiyama H, Fujiwara M, Oka S, Takiguchi 24. M. Functionally impaired HIV-Specific CD8 T cells show high affinity TCR-ligand interactions. J Immunol. 2004;173(9):5451-7.

  14. Sibener LV, Fernandes RA, Kolawole EM, Carbone CB, 25. Liu F, Mcaffee D, Birnbaum ME, Yang X, Su LF, Yu W, Dong S, Gee MH, Jude KM, Davis MM, Groves JT, Goddard WA 3rd, Heath JR, Evavold BD, Vale RD, Garcia KC. Isolation of a structural mechanism for uncoupling T 26. cell receptor signaling from peptide-MHC binding. Cell. 2018;174(3):672-87.

  15. Liu B, Chen W, Evavold BD, Zhu C. Accumulation of dynamic catch bonds between TCR and agonist peptide-MHC triggers T cell signaling. Cell. 2014;157(2):357-68.

  16. Hong J, Persaud SP, Horvath S, Allen PM, Evavold BD, Zhu C. Force-regulated in situ TCR-peptide-bound MHC class II kinetics determine functions of CD4+ T cells. J Immunol. 2015;195(8):3557-64.

  17. Stirnweiss A, Hartig R, Gieseler S, Lindquist JA, Reichardt P, Philipsen L, Simeoni L, Poltorak M, Merten C, Zuschratter W, Prokazov Y, Paster W, Stockinger H, Harder T, Gunzer M, Schraven B. T cell activation results in conformational changes in the Src family kinase Lck to induce its activation. Sci Signal. 2013;6(263):ra13.

  18. Kaizuka Y, Douglass AD, Varma R, Dustin ML, Vale RD. Mechanisms for segregating T cell receptor and adhesion molecules during immunological synapse formation in Jurkat T cells. Proc Natl Acad Sci U S A. 2007;104(51):20296-301.

  19. Mcneill L, Salmond RJ, Cooper JC, Carret CK, Cassady-Cain RL, Roche-Molina M, Tandon P, Holmes N, Alexander DR. The differential regulation of Lck kinase phosphorylation sites by CD45 is critical for T cell receptor signaling responses. Immunity. 2007;27(3):425-37.

  20. Giardino Torchia ML, Dutta D, Mittelstadt PR, Guha J, Gaida MM, Fish K, Barr VA, Akpan IO, Samelson LE, Tagad HD, Debnath S, Miller Jenkins LM, Appella E, Ashwell JD. Intensity and duration of TCR signaling is limited by p38 phosphorylation of ZAP-70(T293) and destabilization of the signalosome. Proc Natl Acad Sci U S A. 2018;115(9):2174-9.

  21. Szabo M, Czompoly T, Kvell K, Talaber G, Bartis D, Nemeth P, Berki T, Boldizsar F. Fine-tuning of proximal TCR signaling by ZAP-70 tyrosine residues in Jurkat cells. Int Immunol. 2012;24(2):79-87.

  22. Yablonski D, Kadlecek T, Weiss A. Identification of a phospholipase C-gamma1 (PLC-gamma1) SH3 domain-binding site in SLP-76 required for T-cell receptor-mediated activation of PLC-gamma1 and NFAT. Mol Cell Biol. 2001;21(13):4208-18.

  23. Sun Z, Arendt CW, Ellmeier W, Schaeffer EM, Sunshine MJ, Gandhi L, Annes J, Petrzilka D, Kupfer A, Schwartzberg PL, Littman DR. PKC-theta is required for TCR-induced NF-kappaB activation in mature but not immature T lymphocytes. Nature. 2000;404(6776):402-7.

  24. Zhong XP, Hainey EA, Olenchock BA, Zhao H, Topham MK, Koretzky GA. Regulation of T cell receptor-induced activation of the Ras-ERK pathway by diacylglycerol kinase zeta. J Biol Chem. 2002;277(34):31089-98.

  25. Villalba M, Bi K, Rodriguez F, Tanaka Y, Schoenberger S, Altman A. Vav1/Rac-dependent actin cytoskeleton reorganization is required for lipid raft clustering in T cells. J Cell Biol. 2001;155(3):331-8.

  26. Hehner SP, Hofmann TG, Dienz O, Droge W, Schmitz ML. Tyrosine-phosphorylated Vav1 as a point of integration for T-cell receptor- and CD28-mediated activation of JNK, p38, and interleukin-2 transcription. J Biol Chem. 2000;275(24):18160-71.

  27. Guy CS, Vignali KM, Temirov J, Bettini ML, Overacre AE, Smeltzer M, Zhang H, Huppa JB, Tsai Y-H, Lobry C, Xie J, Dempsey PJ, Crawford HC, Aifantis I, Davis MM, Vignali DA. Distinct TCR signaling pathways drive proliferation and cytokine production in T cells. Nat Immunol. 2013;14(3):262-70.

  28. Bettini ML, Chou PC, Guy CS, Lee T, Vignali KM, Vignali DA. Cutting edge: CD3 ITAM diversity is required for optimal TCR signaling and thymocyte development. J Immunol. 2017;199(5):1555-60.

  29. Holst J, Wang H, Eder KD, Workman CJ, Boyd KL, Baquet Z, Singh H, Forbes K, Chruscinski A, Smeyne R, Van Oers NS, Utz PJ, Vignali DA. Scalable signaling mediated by T cell antigen receptor-CD3 ITAMs ensures effective negative selection and prevents autoimmunity. Nat Immunol. 2008;9(6):658-6.

  30. James JR. Tuning ITAM multiplicity on T cell receptors can control potency and selectivity to ligand density. Sci Signal. 2018;11(531):eaan1088.

  31. Zheng W, O'Hear CE, Alli R, Basham JH, Abdelsamed HA, Palmer LE, Jones LL, Youngblood B, Geiger TL. PI3K orchestration of the in vivo persistence of chimeric antigen receptor-modified T cells. Leukemia. 2018;32(5):1157-67.

  32. Feucht J, Sun J, Eyquem J, Ho YJ, Zhao Z, Leibold J, Dobrin A, Cabriolu A, Hamieh M, Sadelain M. Calibration of CAR activation potential directs alternative T cell fates and therapeutic potency. Nat Med. 2019;25(1):82-8.

  33. Chang VT, Fernandes RA, Ganzinger KA, Lee SF, Siebold C, McColl J, Jonsson P, Palayret M, Harlos K, Coles CH, Jones EY, Lui Y, Huang E, Gilbert RJC, Klenerman D, Aricescu AR, Davis SJ. Initiation of T cell signaling by CD45 segregation at "close contacts." Nat Immunol. 45. 2016;17(5):574-82.

  34. Choudhuri K, Wiseman D, Brown MH, Gould K, Van Der Merwe PA. T-cell receptor triggering is critically dependent on the dimensions of its peptide-MHC ligand. 46. Nature. 2005;436(7050):578-82.

  35. Galvez J, Galvez JJ, Garcia-Penarrubia P. TCR/pMHC interaction: phenotypic model for an unsolved enigma. Front Immunol. 2016;7(467).

  36. Taylor MJ, Husain K, Gartner ZJ, Mayor S, Vale RD. 47. A DNA-based T cell receptor reveals a role for receptor clustering in ligand discrimination. Cell. 2017;169(1): 108-19.

  37. Stepanek O, Prabhakar AS, Osswald C, King CG, Bulek A, Naeher D, Beaufils-Hugot M, Abanto ML, Galati V, Hausmann B, Lang R, Cole DK, Huseby ES, Sewell AK, Chakraborty AK, Palmer E. Coreceptor scanning by the T cell receptor provides a mechanism for T cell tolerance. Cell. 2014;159(2):333-45.

  38. Philipsen L, Reddycherla AV, Hartig R, Gumz J, Kastle M, Kritikos A, Poltorak MP, Prokazov Y, Turbin E, Weber A, Zuschratter W, Schraven B, Simeoni L, Muller AJ. De novo phosphorylation and conformational opening of the tyrosine kinase Lck act in concert to initiate T cell receptor signaling. Sci Signal. 2017;10(462).

  39. Moogk D, Zhong S, Yu Z, Liadi I, Rittase W, Fang V, Dougherty J, Perez-GarciaA, Osman I, Zhu C, Varadarajan N, Restifo NP, Frey AB, Krogsgaard M. Constitutive Lck activity drives sensitivity differences between CD8+ memory T cell subsets. J Immunol. 2016;197(2):644-54.

  40. Gil D, Schamel WWA, Montoya M, Sanchez-Madrid F, Alarcon B. Recruitment ofNck by CD3e reveals a ligand-induced conformational change essential for T cell receptor signaling and synapse formation. Cell. 2002;109:901-12.

  41. Rangarajan S, He Y, Chen Y, Kerzic MC, Ma B, Gowthaman R, Pierce BG, Nussinov R, Mariuzza RA, Orban J. Peptide-MHC (pMHC) binding to a human antiviral T cell receptor induces long-range allosteric communication between pMHC- and CD3-binding sites. J Biol Chem. 2018;293(41):15991-16005.

  42. Gagnon E, Schubert DA, Gordo S, Chu HH, Wucherpfennig KW. Local changes in lipid environment of TCR microclusters regulate membrane binding by the CD3epsilon cytoplasmic domain. J Exp Med. 2012;209(13):2423-39.

  43. Bettini ML, Guy C, Dash P, Vignali KM, Hamm DE, Dobbins J, Gagnon E, Thomas PG, Wucherpfennig KW, Vignali DA. Membrane association of the CD3epsilon signaling domain is required for optimal T cell development and function. J Immunol. 2014;193(1): 258-67.

  44. Spaulding AR, Salgado-Pabon W, Kohler PL, Horswill AR, Leung DY, Schlievert PM. Staphylococcal and streptococcal superantigen exotoxins. Clin Microbiol Rev. 2013;26(3):422-47.

  45. Yamasaki S, Tachibana M, Shinohara N, Iwashima M. Lck-independent triggering of T-cell antigen receptor signal transduction by staphylococcal enterotoxins. J Biol Chem. 1997;272(23):14787-91.

  46. Shan X, Balakir R, Criado G, Wood JS, Seminario MC, Madrenas J, Wange RL. Zap-70-independent Ca(2+) mobilization and Erk activation in Jurkat T cells in response to T-cell antigen receptor ligation. Mol Cell Biol. 2001;21(21):7137-49.

  47. Bueno C, Lemke CD, Criado G, Baroja ML, Ferguson SS, Rahman AK, Tsoukas CD, Mccormick JK, Madrenas J. Bacterial superantigens bypass Lck-dependent T cell receptor signaling by activating a Galpha11-dependent, PLC-beta-mediated pathway. Immunity. 2006;25(1): 67-78.

  48. Criado G, Madrenas J. Superantigen stimulation reveals the contribution of Lck to negative regulation of T cell activation. J Immunol. 2004;172(1):222-30.

  49. Carter JD, Neel BG, Lorenz U. The tyrosine phosphatase SHP-1 influences thymocyte selection by setting TCR signaling thresholds. Int Immunol. 1999;11(12): 1999-2014.

  50. Hebeisen M, Baitsch L, Presotto D, Baumgaertner P, Romero P, Michielin O, Speiser DE, Rufer N. SHP-1 phosphatase activity counteracts increased T cell receptor affinity. J Clin Invest. 2013;123(3):1044-56.

  51. Li Z, Zeppa JJ, Hancock MA, Mccormick JK, Doherty TM, Hendy GN, Madrenas J. Staphylococcal superantigens use LAMA2 as a coreceptor to activate T cells. J Immunol. 2018;200(4):1471-9.

  52. Fujimaki W, Iwashima M, Yagi J, Zhang H, Yagi H, Seo K, Imai Y, Imanishi K, Uchiyama T. Functional uncoupling of T-cell receptor engagement and Lck activation in anergic human thymic CD4+ T cells. J Biol Chem. 2001;276(20):17455-60.

  53. Xu SX, Mccormick JK. Staphylococcal superantigens in colonization and disease. Front Cell Infect Microbiol. 2012;2(52).

  54. Chau TA, Mccully ML, Brintnell W, An G, Kasper KJ, Vines ED, Kubes P, Haeryfar SM, Mccormick JK, Cairns E, Heinrichs DE, Madrenas J. Toll-like receptor 2 ligands on the staphylococcal cell wall downregulate superantigen-induced T cell activation and prevent toxic shock syndrome. Nat Med. 2009;15(6):641-8.

  55. Peres AG, Stegen C, Li J, Xu AQ, Levast B, Surette MG, Cousineau B, Desrosiers M, Madrenas J. Uncoupling of pro- and anti-inflammatory properties of Staphylococcus aureus. Infect Immun. 2015;83(4):1587-97.

  56. Oosting M, Cheng SC, Bolscher JM, Vestering-Stenger R, Plantinga TS, Verschueren IC, Arts P, Garritsen A, Van Eenennaam H, Sturm P, Kullberg BJ, Hoischen A, Adema GJ, Van Der Meer JW, Netea MG, Joosten LA.Human TLR10 is an anti-inflammatory pattern-recognition receptor. Proc Natl Acad Sci USA. 2014;111(42): E4478-84.

  57. Gervais FG, Chow LM, Lee JM, Branton PE, Veillette A. The SH2 domain is required for stable phosphorylation 70. of p56lck at tyrosine 505, the negative regulatory site. Mol Cell Biol. 1993;13(11):7112-21.

  58. Mustelin T, Altman A. Dephosphorylation and activation of the T cell tyrosine kinase pp56lck by the leukocyte common antigen (CD45). Oncogene. 1990;5(6):809-13.

  59. Li JP, Yang CY, Chuang HC, Lan JL, Chen DY, Chen YM, Wang X, Chen AJ, Belmont JW, Tan TH. The phosphatase JKAP/DUSP22 inhibits T-cell receptor signalling and autoimmunity by inactivating Lck. Nat Commun. 2014;5(3618).

  60. Chiang GG, Sefton BM. Specific dephosphorylation of the Lck tyrosine protein kinase at Tyr-394 by the SHP-1 protein-tyrosine phosphatase. J Biol Chem. 2001;276(25):23173-8.

  61. Lorenz U, Ravichandran KS, Pei D, Walsh CT, Burakoff SJ, Neel BG. Lck-dependent tyrosyl phosphorylation of the phosphotyrosine phosphatase SH-PTP1 in murine T cells. Mol Cell Biol. 1994;14(3):1824-34.

  62. Paster W, Bruger AM, Katsch K, Gregoire C, Roncagalli R, Fu G, Gascoigne NRJ, Nika K, Cohnen A, Feller SM, Simister PC, Molder KC, Cordoba SP, Dushek O, Malissen B, Acuto O. A THEM1S:SHP1 complex promotes T-cell survival. EMBO J. 2015;34(3):393-409.

  63. Choi S, Warzecha C, Zvezdova E, Lee J, Argenty J, Lesourne R, Aravind L, Love PE. THEMIS enhances TCR signaling and enables positive selection by selective inhibition of the phosphatase SHP-1. Nat Immunol. 2017;18(4):433-41.

  64. Johnson DJ, Pao LI, Dhanji S, Murakami K, Ohashi PS, Neel BG. Shpl regulates T cell homeostasis by limiting IL-4 signals. J Exp Med. 2013;210(7):1419-31.

  65. Martinez RJ, Morris AB, Neeld DK, Evavold BD. Targeted loss of SHP1 in murine thymocytes dampens TCR signaling late in selection. Eur J Immunol. 2016;46(9):2103-10.

  66. Moon EK, Wang LC, Dolfi DV, Wilson CB, Ranganathan R, Sun J, Kapoor V, Scholler J, Pure E, Milone MC, June CH, Riley JL, Wherry EJ, Albelda SM. Multifactorial T-cell hypofunction that is reversible can limit the efficacy of chimeric antigen receptor-transduced human T cells in solid tumors. Clin Cancer Res. 2014;20(16):4262-73.

  67. Le Page A, Fortin C, Garneau H, Allard N, Tsvetkova K, Tan CT, Larbi A, Dupuis G, Fulop T. Downregulation of inhibitory SRC homology 2 domain-containing 81. phosphatase-1 (SHP-1) leads to recovery of T cell responses in elderly. Cell Commun Signal. 2014;12(2).

  68. Stefanova I, Hemmer B, Vergelli M, Martin R, Biddison WE, Germain RN. TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback 82. pathways. Nat Immunol. 2003;4(3):248-54.

  69. Wasserman HA, Beal CD, Zhang Y, Jiang N, Zhu C, Evavold BD. MHC variant peptide-mediated anergy of encephalitogenic T cells requires SHP-1. J Immunol. 2008;181(10):6843-9.

  70. Mercadante ER, Lorenz UM. T cells deficient in the tyrosine phosphatase SHP-1 resist suppression by regulatory T cells. J Immunol. 2017;199(1):129-37.

  71. Getahun A, Beavers NA, Larson SR, Shlomchik MJ, Cambier JC. Continuous inhibitory signaling by both SHP-1 and SHIP-1 pathways is required to maintain unresponsiveness of anergic B cells. J Exp Med. 2016;213(5):751-69.

  72. De Magistris MT, Alexander J, Coggeshall M, Altman A, Gaeta FC, Grey HM, Sette A. Antigen analog-major histocompatibility complexes act as antagonists of the T cell receptor. Cell. 1992;68(4):625-34.

  73. Madrenas J, Wange RL, Wang JL, Isakov N, Samelson LE, Germain RN. Zeta phosphorylation without ZAP-70 activation induced by TCR antagonists or partial agonists. Science. 1995;267(5197):515-8.

  74. Blank U, Launay P, Benhamou M, Monteiro RC. Inhibitory ITAMs as novel regulators of immunity. Immunol Rev. 2009;232(1):59-71.

  75. Mkaddem SB, Murua A, Flament H, Titeca-Beauport D, Bounaix C, Danelli L, Launay P, Benhamou M, Blank U, Daugas E, Charles N, Monteiro RC. Lyn and Fyn function as molecular switches that control immunoreceptors to direct homeostasis or inflammation. Nat Commun. 2017;8(1):246.

  76. Jones ML, Craik JD, Gibbins JM, Poole AW. Regulation of SHP-1 tyrosine phosphatase in human platelets by serine phosphorylation at its C terminus. J Biol Chem. 2004;279(39):40475-83.

  77. Liu Y, Kruhlak MJ, Hao JJ, Shaw S. Rapid T cell receptor-mediated SHP-1 S591 phosphorylation regulates SHP-1 cellular localization and phosphatase activity. J Leukoc Biol. 2007;82(3):742-51.

  78. Ishikawa E, Kosako H, Yasuda T, Ohmuraya M, Araki K, Kurosaki T, Saito T, Yamasaki S. Protein kinase D regulates positive selection of CD4(+) thymocytes through phosphorylation of SHP-1. Nat Commun. 2016;7:12756.

  79. Ebner P, Versteeg GA, Ikeda F. Ubiquitin enzymes in the regulation of immune responses. Crit Rev Biochem Mol Biol. 2017;52(4):425-60.

  80. Huang H, Jeon MS, Liao L, Yang C, Elly C, Yates JR 3rd, Liu YC. K33-linked polyubiquitination of T cell receptor-zeta regulates proteolysis-independent T cell signaling. Immunity. 2010;33(1):60-70.

  81. Nurieva RI, Zheng S, Jin W, Chung Y, Zhang Y, Martinez GJ, Reynolds JM, Wang SL, Lin X, Sun SC, Lozano G, Dong C. The E3 ubiquitin ligase GRAIL regulates T cell tolerance and regulatory T cell function by mediating T cell receptor-CD3 degradation. Immunity. 2010;32(5):670-80.

  82. Carpino N, Chen Y, Nassar N, Oh HW. The Sts proteins target tyrosine phosphorylated, ubiquitinated proteins within TCR signaling pathways. Mol Immunol. 2009;46(16):3224-31.

  83. Ivanova E, Carpino N. Negative regulation of TCR signaling by ubiquitination of Zap-70 Lys-217. Mol Immunol. 2016;73:19-28.

  84. Hu H, Wang H, Xiao Y, Jin J, Chang JH, Zou Q, Xie X, Cheng X, Sun SC. Otud7b facilitates T cell activation and inflammatory responses by regulating Zap70 ubiquitination. J Exp Med. 2016;213(3):399-414.

  85. Naik E, Dixit VM. Usp9X is required for lymphocyte activation and homeostasis through its control of ZAP70 ubiquitination and PKCbeta kinase activity. J Immunol. 2016;196(8):3438-51.

  86. Balagopalan L, Barr VA, Sommers CL, Barda-Saad M, Goyal A, Isakowitz MS, Samelson LE. c-Cbl-mediated regulation of LAT-nucleated signaling complexes. Mol Cell Biol. 2007;27(24):8622-36.

  87. Guo H, Qiao G, Ying H, Li Z, Zhao Y, Liang Y, Yang L, Lipkowitz S, Penninger JM, Langdon WY, Zhang J. E3 ubiquitin ligase Cbl-b regulates Pten via Nedd4 in T cells independently of its ubiquitin ligase activity. Cell Rep. 2012;1(5):472-82.

  88. Gorska MM, Liang Q, Karim Z, Alam R. Uncoordinated 119 protein controls trafficking of Lck via the Rab11 endosome and is critical for immunological synapse formation. J Immunol. 2009;183(3):1675-84.

  89. Xiao Y, Qiao G, Tang J, Tang R, Guo H, Warwar S, Langdon WY, Tao L, Zhang J. Protein tyrosine phosphatase SHP-1 modulates T cell responses by controlling Cbl-b degradation. J Immunol. 2015;195(9):4218-27.

  90. Azoulay-Alfaguter I, Strazza M, Peled M, Novak HK, Muller J, Dustin ML, Mor A. The tyrosine phosphatase SHP-1 promotes T cell adhesion by activating the adaptor protein CrkII in the immunological synapse. Sci Signal. 2017;10(491).

  91. Lehnert C, Weiswange M, Jeremias I, Bayer C, Grunert M, Debatin KM, Strauss G. TRAIL-receptor costimulation inhibits proximal TCR signaling and suppresses human T cell activation and proliferation. J Immunol. 2014;193(8):402131.

  92. Chyuan IT, Tsai HF, Wu CS, Sung CC, Hsu PN. TRAIL- mediated suppression of T cell receptor signaling inhibits T cell activation and inflammation in experimental autoimmune encephalomyelitis. Front Immunol. 2018;9(15).

  93. Teft WA, Madrenas J. Characterization of oligomers induced by inverse agonists of CTLA-4. Immunol Lett. 2008;120(1-2):29-36.

  94. Ventimiglia LN, Alonso MA. The role of membrane rafts in Lck transport, regulation and signalling in T-cells. Biochem J. 2013;454(2):169-79.

  95. Otahal P, Angelisova P, Hrdinka M, Brdicka T, Novak P, Drbal K, Horejsi V. A new type of membrane raft-like microdomains and their possible involvement in TCR signaling. J Immunol. 2010;184(7):3689-96.

  96. Hashimoto-Tane A, Yokosuka T, Ishihara C, Sakuma M, Kobayashi W, Saito T. T-cell receptor microclusters critical for T-cell activation are formed independently of lipid raft clustering. Mol Cell Biol. 2010;30(14):3421-9.

  97. Diaz-Rohrer BB, Levental KR, Simons K, Levental I. Membrane raft association is a determinant of plasma membrane localization. Proc Natl Acad Sci U S A. 2014;111(23):8500-5.

  98. Hashimoto-Tane A, Saito T. Dynamic regulation of TCR-microclusters and the microsynapse for T cell activation. Front Immunol. 2016;7(255).

  99. Mitsopoulos P, Madrenas J. Identification of multimolecular complexes and supercomplexes in compartment- selective membrane microdomains. Methods Cell Biol. 2013;117:411-431.

  100. Ormonde JVS, Li Z, Stegen C, Madrenas J. TAOK3 regulates canonical TCR signaling by preventing early SHP-1-mediated inactivation of LCK. J Immunol. 2018;201(11):3431-42.

  101. Tassi E, Biesova Z, Di Fiore PP, Gutkind JS, Wong WT. Human JIK, a novel member of the STE20 kinase family that inhibits JNK and is negatively regulated by epidermal growth factor. J Biol Chem. 1999;274(47):33287-95.

  102. Rawat SJ, Chernoff J. Regulation of mammalian Ste20 (Mst) kinases. Trends Biochem Sci. 2015;40(3):149-56.

  103. Chen Z, Raman M, Chen L, Lee SF, Gilman AG, Cobb MH. TAO (thousand-and-one amino acid) protein kinases mediate signaling from carbachol to p38 mitogen-activated protein kinase and ternary complex factors. J Biol Chem. 2003;278(25):22278-83.

  104. Raman M, Earnest S, Zhang K, Zhao Y, Cobb MH. TAO kinases mediate activation of p38 in response to DNA damage. EMBO J. 2007;26(8):2005-14.

  105. Arthur JS, Ley SC. Mitogen-activated protein kinases in innate immunity. Nat Rev Immunol. 2013;13(9):679-92.

  106. Ultanir SK, Yadav S, Hertz NT, Oses-Prieto JA, Claxton S, Burlingame AL, Shokat KM, Jan LY, Jan YN. MST3 kinase phosphorylates TAO1/2 to enable Myosin Va function in promoting spine synapse development. Neuron. 2014;84(5):968-82.

  107. Tavares IA, Touma D, Lynham S, Troakes C, Schober M, Causevic M, Garg R, Noble W, Killick R, Bodi I, Hanger DP, Morris JD. Prostate-derived sterile 20-like kinases (PSKs/TAOKs) phosphorylate tau protein and are activated in tangle-bearing neurons in Alzheimer disease. J Biol Chem. 2013;288(21):15418-29.

  108. Wojtala RL, Tavares IA, Morton PE, Valderrama F, Thomas NS, Morris JD. Prostate-derived sterile 20-like kinases (PSKs/TAOKs) are activated in mitosis and contribute to mitotic cell rounding and spindle positioning. J Biol Chem. 2011;286(34):30161-70.

  109. Shrestha RL, Tamura N, Fries A, Levin N, Clark J, Draviam VM. TAO1 kinase maintains chromosomal stability by facilitating proper congression of chromosomes. Open Biol. 2014;4(6):130108.

  110. Hammad H, Vanderkerken M, Pouliot P, Deswarte K, Toussaint W, Vergote K, Vandersarren L, Janssens S, Ramou I, Savvides SN, Haigh JJ, Hendriks R, Kopf M, Craessaerts K, De Strooper B, Kearney JF, Conrad DH, Lambrecht BN. Transitional B cells commit to marginal zone B cell fate by Taok3-mediated surface expression of ADAM10. Nat Immunol. 2017;18(3):313-20.

  111. Yoneda T, Imaizumi K, Oono K, Yui D, Gomi F, Katayama T, Tohyama M. Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress. J Biol Chem. 2001;276(17):13935-40.

  112. Boggiano JC, Vanderzalm PJ, Fehon RG. Tao-1 phosphorylates Hippo/MST kinases to regulate the Hippo-Salvador-Warts tumor suppressor pathway. Dev Cell. 2011;21(5):888-95.

  113. Zhang W, Chen T, Wan T, He L, Li N, Yuan Z, Cao X. Cloning of DPK, a novel dendritic cell-derived protein kinase activating the ERK1/ERK2 and JNK/ SAPK pathways. Biochem Biophys Res Commun. 2000;274(3):872-9.

  114. Shiloh Y, Ziv Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nature Rev Mol Cell Biol. 2013;14(4):197.

  115. Mackeigan JP, Murphy LO, Blenis J. Sensitized RNAi screen of human kinases and phosphatases identifies new regulators of apoptosis and chemoresistance. Nat Cell Biol. 2005;7(6):591-600.

  116. Wu H, Wei L, Fan F, Ji S, Zhang S, Geng J, Hong L, Fan X, Chen Q, Tian J, Jiang M, Sun X, Jin C, Yin ZY, Liu Q, Zhang J, Qin F, Lin KH, Yu JS, Deng X, Wang HR, Zhao B, Johnson RL, Chen L, Zhou D. Integration of Hippo signalling and the unfolded protein response to restrain liver overgrowth and tumorigenesis. Nat Commun. 2015;6:6239.

  117. Plouffe SW, Meng Z, Lin KC, Lin B, Hong AW, Chun JV, Guan KL. Characterization of hippo pathway components by gene inactivation. Mol Cell. 2016;64(5):993-1008.

  118. Dhanasekaran SM, Balbin OA, Chen G, Nadal E, Kalyana- Sundaram S, Pan J, Veeneman B, Cao X, Malik R, Vats P, Wang R, Huang S, Zhong J, Jing X, Iyer M, Wu YM, Harms PW, Lin J, Reddy R, Brennan C, Palanisamy N, Chang AC, Truini A, Truini M, Robinson DR, Beer DG, Chinnaiyan AM. Transcriptome meta-analysis of lung cancer reveals recurrent aberrations in NRG1 and Hippo pathway genes. Nat Commun. 2014;5:5893.

  119. Koo CY, Giacomini C, Reyes-Corral M, Olmos Y, Tavares IA, Marson CM, Linardopoulos S, Tutt AN, Morris JDH. Targeting TAO kinases using a new inhibitor compound delays mitosis and induces mitotic cell death in centrosome amplified breast cancer cells. Mol Cancer Ther. 2017;16(11):2410-21.

  120. Huang RC, Garratt ES, Pan H, Wu Y, Davis EA, Barton SJ, Burdge GC, Godfrey KM, Holbrook JD, Lillycrop KA. Genome-wide methylation analysis identifies differentially methylated CpG loci associated with severe obesity in childhood. Epigenetics. 2015;10(11):995-1005.

  121. Cook-Sather SD, Li J, Goebel TK, Sussman EM, Rehman MA, Hakonarson H. TAOK3, a novel Genome-Wide Association Study locus associated with morphine requirement and postoperative pain in a retrospective pediatric day surgery population. Pain. 2014;155(9): 1773-83.

  122. Sabio G, Kennedy NJ, Cavanagh-Kyros J, Jung DY, Ko HJ, Ong H, Barrett T, Kim JK, Davis RJ. Role of muscle c-Jun NH2-terminal kinase 1 in obesity-induced insulin resistance. Mol Cell Biol. 2010;30(1):106-15.

  123. Gateva V, Sandling JK, Hom G, Taylor KE, Chung SA, Sun X, Ortmann W, Kosoy R, Ferreira RC, Nordmark G, Gunnarsson I, Svenungsson E, Padyukov L, Sturfelt G, Jonsen A, Bengtsson AA, Rantapaa-Dahlqvist S, Baechler EC, Brown EE, Alarcon GS, Edberg JC, Ramsey-Goldman R, Mcgwin G Jr., Reveille JD, Vila LM, Kimberly RP, Manzi S, Petri MA, Lee A, Gregersen PK, Seldin MF, Ronnblom L, Criswell LA, Syvanen AC, Behrens TW, Graham RR. A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat Genet. 2009;41(11):1228-33.

  124. Hu S, Vissink A, Arellano M, Roozendaal C, Zhou H, Kallenberg CG, Wong DT. Identification of autoantibody biomarkers for primary Sjogren's syndrome using protein microarrays. Proteomics. 2011;11(8):1499-1507.

  125. Both T, Dalm VA, Van Hagen PM, Van Daele PL. Reviewing primary Sjogren's syndrome: beyond the dryness-from pathophysiology to diagnosis and treatment. Int J Med Sci. 2017;14(3):191-200.

  126. Krishnan S, Mali RS, Koehler KR, Vemula S, Chatterjee A, Ghosh J, Ramdas B, Ma P, Hashino E, Kapur R. Class I(A) PI3Kinase regulatory subunit, p85alpha, mediates mast cell development through regulation of growth and survival related genes. PLoS One. 2012;7(1):e28979.

  127. Parry M, Rose-Zerilli MJ, Gibson J, Ennis S, Walewska R, Forster J, Parker H, Davis Z, Gardiner A, Collins A, Oscier DG, Strefford JC. Whole exome sequencing identifies novel recurrently mutated genes in patients with splenic marginal zone lymphoma. PLoS One. 2013;8(12):e83244.

  128. Zhou JY, Krovvidi RK, Gao Y, Gao H, Petritis BO, De AK, Miller-Graziano CL, Bankey PE, Petyuk VA, Nicora CD, Clauss TR, Moore RJ, Shi T, Brown JN, Kaushal A, Xiao W, Davis RW, Maier RV, Tompkins RG, Qian WJ, Camp DG 2nd, Smith RD; Inflammation and the Host Response to Injury Large Scale Collaborative Research Program. Trauma-associated human neutrophil alterations revealed by comparative proteomics profiling. Proteom Clin Appl. 2013;7(7-8):571-83.

  129. Arcaini L, Rossi D, Paulli M. Splenic marginal zone lymphoma: from genetics to management. Blood. 2016;127(17):2072-81.

  130. Li CW, Wang WH, Chen BS. Investigating the specific core 133. genetic and epigenetic networks of cellular mechanisms involved in human aging in peripheral blood mononuclear cells. Oncotarget. 2016;7(8):8556-79.

  131. Zlojutro M, Manz N, Rangaswamy M, Xuei X, Flury- Wetherill L, Koller D, Bierut LJ, Goate A, Hesselbrock V, Kuperman S, Nurnberger J Jr., Rice JP, Schuckit MA, Foroud T, Edenberg HJ, Porjesz B, Almasy L. Genome- 134. Wide Association Study of theta band event-related oscillations identifies serotonin receptor gene HTR7 influencing risk of alcohol dependence. Am J Med Genet B Neuropsychiatr Genet. 2011;156B(1):44-58. 135.

  132. Hennig EE, Mikula M, Rubel T, Dadlez M, Ostrowski J. Comparative kinome analysis to identify putative colon tumor biomarkers. J Mol Med (Berl). 2012;90(4):447-56.

  133. Keng VW, Villanueva A, Chiang DY, Dupuy AJ, Ryan BJ, Matise I, Silverstein KA, Sarver A, Starr TK, Akagi K, Tessarollo L, Collier LS, Powers S, Lowe SW, Jenkins NA, Copeland NG, Llovet JM, Largaespada DA. A conditional transposon-based insertional mutagenesis screen for genes associated with mouse hepatocellular carcinoma. Nat Biotechnol. 2009;27(3):264-74.

  134. Romanuik TL, Wang G, Holt RA, Jones SJ, Marra MA, Sadar MD. Identification of novel androgen-responsive genes by sequencing of LongSAGE libraries. BMC Genom. 2009;10(476).

  135. Bii VM, Collins CP, Hocum JD, Trobridge GD. Replication-incompetent gammaretroviral and lentiviral vector-based insertional mutagenesis screens identify prostate cancer progression genes. Oncotarget. 2018;9(21):15451.

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