Skip to main content

Advertisement

SpringerLink
Log in

Functions of the FAK family kinases in T cells: beyond actin cytoskeletal rearrangement

  • IMMUNOLOGY AT THE UNIVERSITY OF IOWA
  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

T cells control the focus and extent of adaptive immunity in infectious and pathological diseases. The activation of T cells occurs when the T cell antigen receptor (TCR) and costimulatory and/or adhesion receptors are engaged by their ligands. This process drives signaling that promotes cytoskeletal rearrangement and transcription factor activation, both of which regulate the quality and magnitude of the T cell response. However, it is not fully understood how different receptor-induced signals combine to alter T cell activation. The related non-receptor tyrosine kinases focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2) are phosphorylated downstream of the TCR and several costimulatory and adhesion receptors. FAK family proteins integrate receptor-mediated signals that influence actin cytoskeletal rearrangement and effector T cell responses. In this review, we summarize the receptor-specific roles that FAK and Pyk2 control to influence T cell development and activation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Brownlie RJ, Zamoyska R. T cell receptor signalling networks: branched, diversified and bounded. Nat Rev Immunol. 2013;13(4):257–69. doi:10.1038/nri3403.

    Article  CAS  PubMed  Google Scholar 

  2. Smith-Garvin JE, Koretzky GA, Jordan MS. T cell activation. Annu Rev Immunol. 2009;27:591–619. doi:10.1146/annurev.immunol.021908.132706.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Sato T, Tachibana K, Nojima Y, D’Avirro N, Morimoto C. Role of the VLA-4 molecule in T cell costimulation. Identification of the tyrosine phosphorylation pattern induced by the ligation of VLA-4. J Immunol. 1995;155(6):2938–47.

    CAS  PubMed  Google Scholar 

  4. Bartelt RR, Houtman JC. The adaptor protein LAT serves as an integration node for signaling pathways that drive T cell activation. Wiley Interdiscip Rev Syst Biol Med. 2013;5(1):101–10. doi:10.1002/wsbm.1194.

    Article  CAS  PubMed  Google Scholar 

  5. Baaten BJ, Li CR, Bradley LM. Multifaceted regulation of T cells by CD44. Commun Integr Biol. 2010;3(6):508–12. doi:10.4161/cib.3.6.13495.

    Article  PubMed Central  PubMed  Google Scholar 

  6. Udagawa T, Woodside DG, McIntyre BW. Alpha 4 beta 1 (CD49d/CD29) integrin costimulation of human T cells enhances transcription factor and cytokine induction in the absence of altered sensitivity to anti-CD3 stimulation. J Immunol. 1996;157(5):1965–72.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  8. Chapman NM, Yoder AN, Houtman JC. Non-catalytic functions of Pyk2 and Fyn regulate late stage adhesion in human T cells. PLoS ONE. 2012;7(12):e53011. doi:10.1371/journal.pone.0053011.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Collins M, Bartelt RR, Houtman JC. 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.

    Article  CAS  PubMed  Google Scholar 

  10. Collins M, Tremblay M, Chapman N, Curtiss M, Rothman PB, Houtman JC. The T cell receptor- mediated phosphorylation of Pyk2 tyrosines 402 and 580 occurs via a distinct mechanism than other receptor systems. J Leukoc Biol. 2010;87(4):691–701.

    Article  CAS  PubMed  Google Scholar 

  11. Tabassam FH, Umehara H, Huang JY, Gouda S, Kono T, Okazaki T, et al. Beta2-integrin, LFA-1, and TCR/CD3 synergistically induce tyrosine phosphorylation of focal adhesion kinase (pp125(FAK)) in PHA-activated T cells. Cell Immunol. 1999;193(2):179–84.

    Article  CAS  PubMed  Google Scholar 

  12. Ostergaard HL, Ma EA. Fibronectin induces phosphorylation of a 120-kDa protein and synergizes with the T cell receptor to activate cytotoxic T cell clones. Eur J Immunol. 1995;25(1):252–6. doi:10.1002/eji.1830250141.

    Article  CAS  PubMed  Google Scholar 

  13. Dikic I, Dikic I, Schlessinger J. Identification of a new Pyk2 isoform implicated in chemokine and antigen receptor signaling. J Biol Chem. 1998;273(23):14301–8.

    Article  CAS  PubMed  Google Scholar 

  14. Li R, Wong N, Jabali MD, Johnson P. CD44-initiated cell spreading induces Pyk2 phosphorylation, is mediated by Src family kinases, and is negatively regulated by CD45. J Biol Chem. 2001;276(31):28767–73.

    Article  CAS  PubMed  Google Scholar 

  15. Miyazaki T, Takaoka A, Nogueira L, Dikic I, Fujii H, Tsujino S, et al. Pyk2 is a downstream mediator of the IL-2 receptor-coupled Jak signaling pathway. Genes Dev. 1998;12(6):770–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Ma EA, Lou O, Berg NN, Ostergaard HL. Cytotoxic T lymphocytes express a beta3 integrin which can induce the phosphorylation of focal adhesion kinase and the related PYK-2. Eur J Immunol. 1997;27(1):329–35. doi:10.1002/eji.1830270147.

    Article  CAS  PubMed  Google Scholar 

  17. Doucey MA, Legler DF, Faroudi M, Boucheron N, Baumgaertner P, Naeher D, et al. The beta1 and beta3 integrins promote T cell receptor-mediated cytotoxic T lymphocyte activation. J Biol Chem. 2003;278(29):26983–91.

    Article  CAS  PubMed  Google Scholar 

  18. Maguire JE, Danahey KM, Burkly LC, van Seventer GA. T cell receptor- and beta 1 integrin- mediated signals synergize to induce tyrosine phosphorylation of focal adhesion kinase (pp125FAK) in human T cells. J Exp Med. 1995;182(6):2079–90.

    Article  CAS  PubMed  Google Scholar 

  19. Ostergaard HL, Lysechko TL. Focal adhesion kinase-related protein tyrosine kinase Pyk2 in T-cell activation and function. Immunol Res. 2005;31(3):267–82.

    Article  CAS  PubMed  Google Scholar 

  20. Wong NK, Lai JC, Maeshima N, Johnson P. CD44-mediated elongated T cell spreading requires Pyk2 activation by Src family kinases, extracellular calcium, phospholipase C and phosphatidylinositol-3 kinase. Cell Signal. 2011;23(5):812–9. doi:10.1016/j.cellsig.2011.01.003.

    Article  CAS  PubMed  Google Scholar 

  21. Krawczyk C, Oliveira-dos-Santos A, Sasaki T, Griffiths E, Ohashi PS, Snapper S, et al. Vav1 controls integrin clustering and MHC/peptide-specific cell adhesion to antigen-presenting cells. Immunity. 2002;16(3):331–43.

    Article  CAS  PubMed  Google Scholar 

  22. Sasaki H, Nagura K, Ishino M, Tobioka H, Kotani K, Sasaki T. Cloning and characterization of cell adhesion kinase beta, a novel protein-tyrosine kinase of the focal adhesion kinase subfamily. J Biol Chem. 1995;270(36):21206–19.

    Article  CAS  PubMed  Google Scholar 

  23. Ganju RK, Hatch WC, Avraham H, Ona MA, Druker B, Avraham S, et al. RAFTK, a novel member of the focal adhesion kinase family, is phosphorylated and associates with signaling molecules upon activation of mature T lymphocytes. J Exp Med. 1997;185(6):1055–63.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Yu H, Li X, Marchetto GS, Dy R, Hunter D, Calvo B, et al. Activation of a novel calcium-dependent protein-tyrosine kinase. Correlation with c-Jun N-terminal kinase but not mitogen-activated protein kinase activation. J Biol Chem. 1996;271(47):29993–8.

    Article  CAS  PubMed  Google Scholar 

  25. Herzog H, Nicholl J, Hort YJ, Sutherland GR, Shine J. Molecular cloning and assignment of FAK2, a novel human focal adhesion kinase, to 8p11.2–p22 by nonisotopic in situ hybridization. Genomics. 1996;32(3):484–6. doi:10.1006/geno.1996.0149.

    Article  CAS  PubMed  Google Scholar 

  26. Avraham S, Avraham H. Characterization of the novel focal adhesion kinase RAFTK in hematopoietic cells. Leuk Lymphoma. 1997;27(3–4):247–56. doi:10.3109/10428199709059681.

    CAS  PubMed  Google Scholar 

  27. Xiong WC, Macklem M, Parsons JT. Expression and characterization of splice variants of PYK2, a focal adhesion kinase-related protein. J Cell Sci. 1998;111(Pt 14):1981–91.

    CAS  PubMed  Google Scholar 

  28. Li X, Hunter D, Morris J, Haskill JS, Earp HS. A calcium-dependent tyrosine kinase splice variant in human monocytes. Activation by a two-stage process involving adherence and a subsequent intracellular signal. J Biol Chem. 1998;273(16):9361–4.

    Article  CAS  PubMed  Google Scholar 

  29. Hall JE, Fu W, Schaller MD. Focal adhesion kinase: exploring Fak structure to gain insight into function. Int Rev Cell Mol Biol. 2011;288:185–225. doi:10.1016/B978-0-12-386041-5.00005-4.

    Article  CAS  PubMed  Google Scholar 

  30. Frame MC, Patel H, Serrels B, Lietha D, Eck MJ. The FERM domain: organizing the structure and function of FAK. Nat Rev Mol Cell Biol. 2010;11(11):802–14. doi:10.1038/nrm2996.

    Article  CAS  PubMed  Google Scholar 

  31. Cance WG, Kurenova E, Marlowe T, Golubovskaya V. Disrupting the scaffold to improve focal adhesion kinase-targeted cancer therapeutics. Sci Signal. 2013;6(268):pe10. doi:10.1126/scisignal.2004021.

    Article  PubMed Central  PubMed  Google Scholar 

  32. Katagiri T, Takahashi T, Sasaki T, Nakamura S, Hattori S. Protein-tyrosine kinase Pyk2 is involved in interleukin-2 production by Jurkat T cells via its tyrosine 402. J Biol Chem. 2000;275(26):19645–52. doi:10.1074/jbc.M909828199.

    Article  CAS  PubMed  Google Scholar 

  33. Gismondi A, Jacobelli J, Strippoli R, Mainiero F, Soriani A, Cifaldi L, et al. Proline-rich tyrosine kinase 2 and Rac activation by chemokine and integrin receptors controls NK cell transendothelial migration. J Immunol. 2003;170(6):3065–73.

    Article  CAS  PubMed  Google Scholar 

  34. Franklin RA, Atherfold PA, Robinson PJ, Bonner D. Regulation of Pyk2 expression by p56(Lck) in Jurkat T lymphocytes. Cell Signal. 2001;13(1):65–9.

    Article  CAS  PubMed  Google Scholar 

  35. Schaller MD. Cellular functions of FAK kinases: insight into molecular mechanisms and novel functions. J Cell Sci. 2010;123(Pt 7):1007–13. doi:10.1242/jcs.045112.

    Article  CAS  PubMed  Google Scholar 

  36. Fukai I, Hussey RE, Sunder-Plassmann R, Reinherz EL. A critical role for p59(fyn) in CD2-based signal transduction. Eur J Immunol. 2000;30(12):3507–15. doi:10.1002/1521.

    Article  CAS  PubMed  Google Scholar 

  37. Qian D, Lev S, van Oers NS, Dikic I, Schlessinger J, Weiss A. Tyrosine phosphorylation of Pyk2 is selectively regulated by Fyn during TCR signaling. J Exp Med. 1997;185(7):1253–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Wiemer AJ, Wernimont SA, Cung TD, Bennin DA, Beggs HE, Huttenlocher A. The focal adhesion kinase inhibitor PF-562,271 impairs primary CD4+ T cell activation. Biochem Pharmacol. 2013;. doi:10.1016/j.bcp.2013.07.024.

    PubMed Central  PubMed  Google Scholar 

  39. Lysechko TL, Cheung SM, Ostergaard HL. Regulation of the tyrosine kinase Pyk2 by calcium is through production of reactive oxygen species in cytotoxic T lymphocytes. J Biol Chem. 2010;285(41):31174–84. doi:10.1074/jbc.M110.118265.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Tsuchida M, Knechtle SJ, Hamawy MM. CD28 ligation induces tyrosine phosphorylation of Pyk2 but not Fak in Jurkat T cells. J Biol Chem. 1999;274(10):6735–40.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. van Seventer GA, Mullen MM, van Seventer JM. Pyk2 is differentially regulated by beta1 integrin- and CD28-mediated co-stimulation in human CD4+ T lymphocytes. Eur J Immunol. 1998;28(11):3867–77.

    Article  PubMed  Google Scholar 

  43. Damle NK, Aruffo A. Vascular cell adhesion molecule 1 induces T-cell antigen receptor-dependent activation of CD4+ T lymphocytes. Proc Natl Acad Sci USA. 1991;88(15):6403–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Springer TA, Dustin ML. Integrin inside-out signaling and the immunological synapse. Curr Opin Cell Biol. 2012;24(1):107–15. doi:10.1016/j.ceb.2011.10.004.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Nojima Y, Tachibana K, Sato T, Schlossman SF, Morimoto C. Focal adhesion kinase (pp125FAK) is tyrosine phosphorylated after engagement of alpha 4 beta 1 and alpha 5 beta 1 integrins on human T- lymphoblastic cells. Cell Immunol. 1995;161(1):8–13. doi:10.1006/cimm.1995.1002.

    Article  CAS  PubMed  Google Scholar 

  46. Iwata S, Ohashi Y, Kamiguchi K, Morimoto C. Beta 1-integrin-mediated cell signaling in T lymphocytes. J Dermatol Sci. 2000;23(2):75–86.

    Article  CAS  PubMed  Google Scholar 

  47. Rose DM, Liu S, Woodside DG, Han J, Schlaepfer DD, Ginsberg MH. Paxillin binding to the alpha 4 integrin subunit stimulates LFA-1 (integrin alpha L beta 2)-dependent T cell migration by augmenting the activation of focal adhesion kinase/proline-rich tyrosine kinase-2. J Immunol. 2003;170(12):5912–8.

    Article  CAS  PubMed  Google Scholar 

  48. Rodriguez-Fernandez JL, Gomez M, Luque A, Hogg N, Sanchez-Madrid F, Cabanas C. The interaction of activated integrin lymphocyte function-associated antigen 1 with ligand intercellular adhesion molecule 1 induces activation and redistribution of focal adhesion kinase and proline-rich tyrosine kinase 2 in T lymphocytes. Mol Biol Cell. 1999;10(6):1891–907.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Rodriguez-Fernandez JL, Sanchez-Martin L, de Frutos CA, Sancho D, Robinson M, Sanchez-Madrid F, et al. LFA-1 integrin and the microtubular cytoskeleton are involved in the Ca(2)(+)-mediated regulation of the activity of the tyrosine kinase PYK2 in T cells. J Leukoc Biol. 2002;71(3):520–30.

    CAS  PubMed  Google Scholar 

  50. Rodriguez-Fernandez JL, Sanchez-Martin L, Rey M, Vicente-Manzanares M, Narumiya S, Teixido J, et al. Rho and Rho-associated kinase modulate the tyrosine kinase PYK2 in T-cells through regulation of the activity of the integrin LFA-1. J Biol Chem. 2001;276(44):40518–27. doi:10.1074/jbc.M102896200.

    Article  CAS  PubMed  Google Scholar 

  51. Dustin ML, Depoil D. New insights into the T cell synapse from single molecule techniques. Nat Rev Immunol. 2011;11(10):672–84. doi:10.1038/nri3066.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Beemiller P, Krummel MF. Mediation of T-cell activation by actin meshworks. Cold Spring Harb Perspect Biol. 2010;2(9):a002444. doi:10.1101/cshperspect.a002444.

    Article  PubMed Central  PubMed  Google Scholar 

  53. Chapman NM, Connolly SF, Reinl EL, Houtman JC. Focal adhesion kinase negatively regulates lck function downstream of the T cell antigen receptor. J Immunol. 2013;191(12):6208–21. doi:10.4049/jimmunol.1301587.

    Article  CAS  PubMed  Google Scholar 

  54. Garron ML, Arthos J, Guichou JF, McNally J, Cicala C, Arold ST. Structural basis for the interaction between focal adhesion kinase and CD4. J Mol Biol. 2008;375(5):1320–8.

    Article  CAS  PubMed  Google Scholar 

  55. Sancho D, Montoya MC, Monjas A, Gordon-Alonso M, Katagiri T, Gil D, et al. TCR engagement induces proline-rich tyrosine kinase-2 (Pyk2) translocation to the T cell-APC interface independently of Pyk2 activity and in an immunoreceptor tyrosine-based activation motif-mediated fashion. J Immunol. 2002;169(1):292–300.

    Article  CAS  PubMed  Google Scholar 

  56. Finkelstein LD, Shimizu Y, Schwartzberg PL. Tec kinases regulate TCR-mediated recruitment of signaling molecules and integrin-dependent cell adhesion. J Immunol. 2005;175(9):5923–30.

    Article  CAS  PubMed  Google Scholar 

  57. St-Pierre J, Lysechko TL, Ostergaard HL. Hypophosphorylated and inactive Pyk2 associates with paxillin at the microtubule organizing center in hematopoietic cells. Cell Signal. 2011;23(4):718–30. doi:10.1016/j.cellsig.2010.12.006.

    Article  CAS  PubMed  Google Scholar 

  58. Huse M. Microtubule-organizing center polarity and the immunological synapse: protein kinase C and beyond. Front Immunol. 2012;3:235. doi:10.3389/fimmu.2012.00235.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Ostergaard HL, Lou O, Arendt CW, Berg NN. Paxillin phosphorylation and association with Lck and Pyk2 in anti-CD3- or anti-CD45-stimulated T cells. J Biol Chem. 1998;273(10):5692–6.

    Article  CAS  PubMed  Google Scholar 

  60. Faure C, Ramos M, Girault JA. Pyk2 cytonuclear localization: mechanisms and regulation by serine dephosphorylation. CMLS. 2013;70(1):137–52. doi:10.1007/s00018-012-1075-5.

    Article  CAS  PubMed  Google Scholar 

  61. Naito T, Tanaka H, Naoe Y, Taniuchi I. Transcriptional control of T-cell development. Int Immunol. 2011;23(11):661–8. doi:10.1093/intimm/dxr078.

    Article  CAS  PubMed  Google Scholar 

  62. Wiegers GJ, Kaufmann M, Tischner D, Villunger A. Shaping the T-cell repertoire: a matter of life and death. Immunol Cell Biol. 2011;89(1):33–9. doi:10.1038/icb.2010.127.

    Article  PubMed  Google Scholar 

  63. Kanazawa S, Ilic D, Hashiyama M, Noumura T, Yamamoto T, Suda T, et al. p59fyn-p125FAK cooperation in development of CD4+CD8+ thymocytes. Blood. 1996;87(3):865–70.

    CAS  PubMed  Google Scholar 

  64. Ilic D, Furuta Y, Kanazawa S, Takeda N, Sobue K, Nakatsuji N, et al. Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice. Nature. 1995;377(6549):539–44.

    Article  CAS  PubMed  Google Scholar 

  65. Okigaki M, Davis C, Falasca M, Harroch S, Felsenfeld DP, Sheetz MP, et al. Pyk2 regulates multiple signaling events crucial for macrophage morphology and migration. Proc Natl Acad Sci USA. 2003;100(19):10740–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Beinke S, Phee H, Clingan JM, Schlessinger J, Matloubian M, Weiss A. Proline-rich tyrosine kinase-2 is critical for CD8 T-cell short-lived effector fate. Proc Natl Acad Sci USA. 2010;107(37):16234–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  67. Tsuchida M, Manthei ER, Alam T, Knechtle SJ, Hamawy MM. T cell activation up-regulates the expression of the focal adhesion kinase Pyk2: opposing roles for the activation of protein kinase C and the increase in intracellular Ca2+. J Immunol. 1999;163(12):6640–50.

    CAS  PubMed  Google Scholar 

  68. Sieg DJ, Ilic D, Jones KC, Damsky CH, Hunter T, Schlaepfer DD. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  69. Weis SM, Lim ST, Lutu-Fuga KM, Barnes LA, Chen XL, Gothert JR, et al. Compensatory role for Pyk2 during angiogenesis in adult mice lacking endothelial cell FAK. J Cell Biol. 2008;181(1):43–50.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  70. Davidson D, Shi X, Zhong MC, Rhee I, Veillette A. The phosphatase PTP-PEST promotes secondary T cell responses by dephosphorylating the protein tyrosine kinase Pyk2. Immunity. 2010;33(2):167–80. doi:10.1016/j.immuni.2010.08.001.

    Article  CAS  PubMed  Google Scholar 

  71. Valdor R, Macian F. Induction and stability of the anergic phenotype in T cells. Semin Immunol. 2013;25(4):313–20. doi:10.1016/j.smim.2013.10.010.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. Sabe H, Hata A, Okada M, Nakagawa H, Hanafusa H. Analysis of the binding of the Src homology 2 domain of Csk to tyrosine-phosphorylated proteins in the suppression and mitotic activation of c-Src. Proc Natl Acad Sci USA. 1994;91(9):3984–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. Cloutier JF, Chow LM, Veillette A. Requirement of the SH3 and SH2 domains for the inhibitory function of tyrosine protein kinase p50csk in T lymphocytes. Mol Cell Biol. 1995;15(11):5937–44.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  74. Vang T, Abrahamsen H, Myklebust S, Enserink J, Prydz H, Mustelin T, et al. Knockdown of C- terminal Src kinase by siRNA-mediated RNA interference augments T cell receptor signaling in mature T cells. Eur J Immunol. 2004;34(8):2191–9. doi:10.1002/eji.200425036.

    Article  CAS  PubMed  Google Scholar 

  75. Schoenborn JR, Tan YX, Zhang C, Shokat KM, Weiss A. Feedback circuits monitor and adjust basal Lck-dependent events in T cell receptor signaling. Sci Signal. 2011;4(190):ra59. doi:10.1126/scisignal.2001893.

    Article  PubMed Central  PubMed  Google Scholar 

  76. Bergman M, Joukov V, Virtanen I, Alitalo K. Overexpressed Csk tyrosine kinase is localized in focal adhesions, causes reorganization of alpha v beta 5 integrin, and interferes with HeLa cell spreading. Mol Cell Biol. 1995;15(2):711–22.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  77. Songyang Z, Shoelson SE, McGlade J, Olivier P, Pawson T, Bustelo XR, et al. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  78. McShan GD, Zagozdzon R, Park SY, Zrihan-Licht S, Fu Y, Avraham S, et al. Csk homologous kinase associates with RAFTK/Pyk2 in breast cancer cells and negatively regulates its activation and breast cancer cell migration. Int J Oncol. 2002;21(1):197–205.

    CAS  PubMed  Google Scholar 

  79. Bunnell SC, Kapoor V, Trible RP, Zhang W, Samelson LE. Dynamic actin polymerization drives T cell receptor-induced spreading: a role for the signal transduction adaptor LAT. Immunity. 2001;14(3):315–29.

    Article  CAS  PubMed  Google Scholar 

  80. Ren XR, Du QS, Huang YZ, Ao SZ, Mei L, Xiong WC. Regulation of CDC42 GTPase by proline- rich tyrosine kinase 2 interacting with PSGAP, a novel pleckstrin homology and Src homology 3 domain containing rhoGAP protein. J Cell Biol. 2001;152(5):971–84.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  81. Bashour KT, Gondarenko A, Chen H, Shen K, Liu X, Huse M, et al. CD28 and CD3 have complementary roles in T-cell traction forces. Proc Natl Acad Sci USA. 2014;111(6):2241–6. doi:10.1073/pnas.1315606111.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  82. Judokusumo E, Tabdanov E, Kumari S, Dustin ML, Kam LC. Mechanosensing in T lymphocyte activation. Biophys J. 2012;102(2):L5–7. doi:10.1016/j.bpj.2011.12.011.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  83. Babich A, Li S, O’Connor RS, Milone MC, Freedman BD, Burkhardt JK. F-actin polymerization and retrograde flow drive sustained PLCgamma1 signaling during T cell activation. J Cell Biol. 2012;197(6):775–87. doi:10.1083/jcb.201201018.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  84. Tse KW, Lin KB, Dang-Lawson M, Guzman-Perez A, Aspnes GE, Buckbinder L, et al. Small molecule inhibitors of the Pyk2 and FAK kinases modulate chemoattractant-induced migration, adhesion and Akt activation in follicular and marginal zone B cells. Cell Immunol. 2012;275(1–2):47–54. doi:10.1016/j.cellimm.2012.03.002.

    Article  CAS  PubMed  Google Scholar 

  85. Morimoto C, Kobayashi H, Nishijima R, Tanaka H, Iwata S. Role of the beta1 integrin molecule in T- cell activation and migration. Mod Rheumatol. 2000;10(1):8–15. doi:10.3109/s101650070032.

    Article  CAS  PubMed  Google Scholar 

  86. Segarra M, Vilardell C, Matsumoto K, Esparza J, Lozano E, Serra-Pages C, et al. Dual function of focal adhesion kinase in regulating integrin-induced MMP-2 and MMP-9 release by human T lymphoid cells. FASEB J. 2005;19(13):1875–7. doi:10.1096/fj.04-3574fje.

    Article  PubMed  Google Scholar 

  87. Giannoni E, Chiarugi P, Cozzi G, Magnelli L, Taddei ML, Fiaschi T, et al. Lymphocyte function- associated antigen-1-mediated T cell adhesion is impaired by low molecular weight phosphotyrosine phosphatase-dependent inhibition of FAK activity. J Biol Chem. 2003;278(38):36763–76. doi:10.1074/jbc.M302686200.

    Article  CAS  PubMed  Google Scholar 

  88. Sabatos CA, Doh J, Chakravarti S, Friedman RS, Pandurangi PG, Tooley AJ, et al. A synaptic basis for paracrine interleukin-2 signaling during homotypic T cell interaction. Immunity. 2008;29(2):238–48. doi:10.1016/j.immuni.2008.05.017.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  89. Chang JT, Palanivel VR, Kinjyo I, Schambach F, Intlekofer AM, Banerjee A, et al. Asymmetric T lymphocyte division in the initiation of adaptive immune responses. Science. 2007;315(5819):1687–91. doi:10.1126/science.1139393.

    Article  CAS  PubMed  Google Scholar 

  90. Gismondi A, Jacobelli J, Mainiero F, Paolini R, Piccoli M, Frati L, et al. Cutting edge: functional role for proline-rich tyrosine kinase 2 in NK cell-mediated natural cytotoxicity. J Immunol. 2000;164(5):2272–6.

    Article  CAS  PubMed  Google Scholar 

  91. Sancho D, Nieto M, Llano M, Rodriguez-Fernandez JL, Tejedor R, Avraham S, et al. The tyrosine kinase PYK-2/RAFTK regulates natural killer (NK) cell cytotoxic response, and is translocated and activated upon specific target cell recognition and killing. J Cell Biol. 2000;149(6):1249–62.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  92. Cheung R, Malik M, Ravyn V, Tomkowicz B, Ptasznik A, Collman RG. An arrestin-dependent multi-kinase signaling complex mediates MIP-1beta/CCL4 signaling and chemotaxis of primary human macrophages. J Leukoc Biol. 2009;86(4):833–45. doi:10.1189/jlb.0908551.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  93. Rumsey LM, Teague RM, Benedict SH, Chan MA. MIP-1alpha induces activation of phosphatidylinositol-3 kinase that associates with Pyk-2 and is necessary for B-cell migration. Exp Cell Res. 2001;268(1):77–83. doi:10.1006/excr.2001.5272.

    Article  CAS  PubMed  Google Scholar 

  94. Cipolla L, Consonni A, Guidetti G, Canobbio I, Okigaki M, Falasca M, et al. The proline-rich tyrosine kinase Pyk2 regulates platelet integrin alphaIIbbeta3 outside-in signaling. JTH. 2013;11(2):345–56. doi:10.1111/jth.12099.

    CAS  PubMed  Google Scholar 

  95. Jeon MS, Atfield A, Venuprasad K, Krawczyk C, Sarao R, Elly C, et al. Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction. Immunity. 2004;21(2):167–77. doi:10.1016/j.immuni.2004.07.013.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by a Pre-doctoral Fellowship (11PRE7390070 to N.M.C.) and a Scientist’s Development Grant (0830244N to J.C.D.H) from the American Heart Association. Additional support from the National Institutes of Health (T32 AI008595 to N.M.C. and ROI CA136729 from J.C.D.H.) also funded this work.

Author information

Author notes

  1. Nicole M. Chapman

    Present address: Department of Immunology, MS 351, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA

Authors and Affiliations

  1. Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA, 52242, USA

    Nicole M. Chapman & Jon C. D. Houtman

  2. Department of Microbiology, University of Iowa, 2220 MERF, Iowa City, IA, 52242, USA

    Jon C. D. Houtman

Authors
  1. Nicole M. Chapman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jon C. D. Houtman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jon C. D. Houtman.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chapman, N.M., Houtman, J.C.D. Functions of the FAK family kinases in T cells: beyond actin cytoskeletal rearrangement. Immunol Res 59, 23–34 (2014). https://doi.org/10.1007/s12026-014-8527-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-014-8527-y

Keywords

Search

Navigation