Acta Neuropathologica

, Volume 108, Issue 3, pp 224–230 | Cite as

Expression of tyrosine kinases FAK and Pyk2 in 331 human astrocytomas

  • A. Gutenberg
  • W. Brück
  • M. Buchfelder
  • H. C. Ludwig
Regular Paper


The progression of malignancy from astrocytomas to glioblastomas remains clinically as well as histopathologically unpredictable. The focal adhesion kinase (FAK) and the proline-rich tyrosine kinase (Pyk2) show a high expression in glioma cell lines and have an influence on increased cell proliferation and migration of glioma cells in vitro and in vivo. The aim of this study was to correlate the coexpression of FAK and Pyk2 to the WHO grade of malignancy in human astrocytomas. Immunohistochemical staining scores of FAK and Pyk2 were analyzed in 331 astrocytomas and correlated to each other and to the WHO grade. Significant coexpression of FAK and Pyk2 in astrocytomas was demonstrated. Pyk2 expression occurred much more frequently and with higher expression scores within the different WHO grades. Beyond this, a significant correlation between the WHO grade of malignancy of astrocytomas and the expression of FAK, as well as of Pyk2, was detected. This connection and the roles of these two tyrosine kinases in the progression of tumors should be confirmed by further studies.


Focal adhesion kinase Proline-rich tyrosine kinase Astrocytomas Coexpression 


  1. 1.
    Agochiya M, Brunton VG, Owens DW, Parkinson EK, Paraskeva C, Keith WN, Frame MC (1999) Increased dosage and amplification of the focal adhesion kinase gene in human cancer cells. Oncogene 18:5646–5653PubMedGoogle Scholar
  2. 2.
    Avraham H, Park SY, Schinkmann K, Avraham S (2000) RAFTK/Pyk2-mediated cellular signalling. Cell Signal 12:123–133CrossRefPubMedGoogle Scholar
  3. 3.
    Avraham HK, Lee TH, Koh Y, Kim TA, Jiang S, Sussman M, Samarel AM, Avraham S (2003) Vascular endothelial growth factor regulates focal adhesion assembly in human brain microvascular endothelial cells through activation of the focal adhesion kinase and related adhesion focal tyrosine kinase. J Biol Chem 278:36661–36668CrossRefPubMedGoogle Scholar
  4. 4.
    Avraham S, London R, Fu Y, Ota S, Hiregowdara D, Li J, Jiang S, Pasztor LM, White RA, Groopman JE (1995) Identification and characterization of a novel related adhesion focal tyrosine kinase (RAFTK) from megakaryocytes and brain. J Biol Chem 270:27742–27751PubMedGoogle Scholar
  5. 5.
    Burgaya F, Menegon A, Menegoz M, Valtorta F, Girault JA (1995) Focal adhesion kinase in rat central nervous system. Eur J Neurosci 7:1810–1821PubMedGoogle Scholar
  6. 6.
    Cance WG, Harris JE, Iacocca MV, Roche E, Yang X, Chang J, Simkins S, Xu L (2000) Immunohistochemical analyses of focal adhesion kinase expression in benign and malignant human breast and colon tissues: correlation with preinvasive and invasive phenotypes. Clin Cancer Res 6:2417–2423PubMedGoogle Scholar
  7. 7.
    Cance WG, Harris JE, Iacocca MV, Roche E, Yang X, Chang J, Simkins S, Xu L (2000) Immunohistochemical analyses of focal adhesion kinase expression in benign and malignant human breast and colon tissues: correlation with preinvasive and invasive phenotypes. Clin Cancer Res 6:2417–2423PubMedGoogle Scholar
  8. 8.
    Cary LA, Chang JF, Guan JL (1996) Stimulation of cell migration by overexpression of focal adhesion kinase and its association with Src and Fyn. J Cell Sci 109:1787–1794Google Scholar
  9. 9.
    Dikic I, Tokiwa G, Lev S, Courtneidge SA, Schlessinger J (1996) Role for Pyk2 and Src in linking G-protein-coupled receptors with MAP kinase activation. Nature 383:547–550PubMedGoogle Scholar
  10. 10.
    Duong LT, Nakamura I, Lakkakorpi PT, Lipfert L, Bett AJ, Rodan GA (2001) Inhibition of osteoclast function by adenovirus expressing antisense protein-tyrosine kinase 2. J Biol Chem 276:7484–7492CrossRefPubMedGoogle Scholar
  11. 11.
    Fernandis AZ, Prasad A, Band H, Klosel R, Ganju RK (2004) Regulation of CXCR4-mediated chemotaxis and chemoinvasion of breast cancer cells. Oncogene 23:157–167CrossRefPubMedGoogle Scholar
  12. 12.
    Gabarra-Niecko V, Schaller MD, Dunty JM (2003) FAK regulates biological processes important for the pathogenesis of cancer. Cancer Metastasis Rev 22:359–374CrossRefPubMedGoogle Scholar
  13. 13.
    Girault JA, Costa A, Derkinderen P, Studler JM, Toutant M (1999) FAK and PYK2/CAKbeta in the nervous system: a link between neuronal activity, plasticity and survival? Trends Neurosci 22:257–263CrossRefPubMedGoogle Scholar
  14. 14.
    Haskell H, Natarajan M, Hecker TP, Ding Q, Stewart J Jr, Grammer JR, Gladson CL (2003) Focal adhesion kinase is expressed in the angiogenic blood vessels of malignant astrocytic tumors in vivo and promotes capillary tube formation of brain microvascular endothelial cells. Clin Cancer Res 9:2157–2165PubMedGoogle Scholar
  15. 15.
    Hauck CR, Sieg DJ, Hsia DA, Loftus JC, Gaarde WA, Monia BP, Schlaepfer DD (2001) Inhibition of focal adhesion kinase expression or activity disrupts epidermal growth factor-stimulated signaling promoting the migration of invasive human carcinoma cells. Cancer Res 61:7079–7090PubMedGoogle Scholar
  16. 16.
    Hauck CR, Hsia DA, Puente XS, Cheresh DA, Schlaepfer DD (2002) FRNK blocks v-Src-stimulated invasion and experimental metastases without effects on cell motility or growth. EMBO J 21:6289–6302CrossRefPubMedGoogle Scholar
  17. 17.
    Hecker TP, Grammer JR, Gillespie GY, Stewart J Jr, Gladson CL (2002) Focal adhesion kinase enhances signaling through the Shc/extracellular signal-regulated kinase pathway in anaplastic astrocytoma tumor biopsy samples. Cancer Res 62:2699–2707PubMedGoogle Scholar
  18. 18.
    Ilic D, Damsky CH, Yamamoto T (1997) Focal adhesion kinase: at the crossroads of signal transduction. J Cell Sci 110:401–407PubMedGoogle Scholar
  19. 19.
    Jones G, Machado J Jr, Tolnay M, Merlo A (2001) PTEN-independent induction of caspase-mediated cell death and reduced invasion by the focal adhesion targeting domain (FAT) in human astrocytic brain tumors which highly express focal adhesion kinase (FAK). Cancer Res 61:5688–5691PubMedGoogle Scholar
  20. 20.
    Lev S, Moreno H, Martinez R, Canoll P, Peles E, Musacchio JM, Plowman GD, Rudy B, Schlessinger J (1995) Protein tyrosine kinase PYK2 involved in Ca(2+)-induced regulation of ion channel and MAP kinase functions. Nature 376:737–745PubMedGoogle Scholar
  21. 21.
    Lipinski CA, Tran NL, Bay C, Kloss J, McDonough WS, Beaudry C, Berens ME, Loftus JC (2003) Differential role of proline-rich tyrosine kinase 2 and focal adhesion kinase in determining glioblastoma migration and proliferation. Mol Cancer Res 1:323–332PubMedGoogle Scholar
  22. 22.
    Maung K, Easty DJ, Hill SP, Bennett DC (1999) Requirement for focal adhesion kinase in tumor cell adhesion. Oncogene 18:6824–6828CrossRefPubMedGoogle Scholar
  23. 23.
    Muir D, Johnson J, Rojiani M, Inglis BA, Rojiani A, Maria BL (1996) Assessment of laminin-mediated glioma invasion in vitro and by glioma tumors engrafted within rat spinal cord. J Neurooncol 30:199–211PubMedGoogle Scholar
  24. 24.
    Okigaki M, Davis C, Falasca M, Harroch S, Felsenfeld DP, Sheetz MP, Schlessinger J (2003) Pyk2 regulates multiple signaling events crucial for macrophage morphology and migration. Proc Natl Acad Sci USA 100:10740–10745CrossRefPubMedGoogle Scholar
  25. 25.
    Owens LV, Xu L, Craven RJ, Dent GA, Weiner TM, Kornberg L, Liu ET, Cance WG (1995) Overexpression of the focal adhesion kinase (p125FAK) in invasive human tumors. Cancer Res 55:2752–2755PubMedGoogle Scholar
  26. 26.
    Owens LV, Xu L, Dent GA, Yang X, Sturge GC, Craven RJ, Cance WG (1996) Focal adhesion kinase as a marker of invasive potential in differentiated human thyroid cancer. Ann Surg Oncol 3:100–105PubMedGoogle Scholar
  27. 27.
    Rutka JT, Muller M, Hubbard SL, Forsdike J, Dirks PB, Jung S, Tsugu A, Ivanchuk S, Costello P, Mondal S, Ackerley C, Becker LE (1999) Astrocytoma adhesion to extracellular matrix: functional significance of integrin and focal adhesion kinase expression. J Neuropathol Exp Neurol 58:198–209PubMedGoogle Scholar
  28. 28.
    Sasaki H, Nagura K, Ishino M, Tobioka H, Kotani K, Sasaki T (1995) Cloning and characterization of cell adhesion kinase beta, a novel protein-tyrosine kinase of the focal adhesion kinase subfamily. J Biol Chem 270:21206–21219CrossRefPubMedGoogle Scholar
  29. 29.
    Slack JK, Adams RB, Rovin JD, Bissonette EA, Stoker CE, Parsons JT (2001) Alterations in the focal adhesion kinase/Src signal transduction pathway correlate with increased migratory capacity of prostate carcinoma cells. Oncogene 20:1152–1163CrossRefPubMedGoogle Scholar
  30. 30.
    Stanzione R, Picascia A, Chieffi P, Imbimbo C, Palmieri A, Mirone V, Staibano S, Franco R, De Rosa G, Schlessinger J, Tramontano D (2001) Variations of proline-rich kinase Pyk2 expression correlate with prostate cancer progression. Lab Invest 81:51–59PubMedGoogle Scholar
  31. 31.
    Tang H, Hao Q, Fitzgerald T, Sasaki T, Landon EJ, Inagami T (2002) Pyk2/CAKbeta tyrosine kinase activity-mediated angiogenesis of pulmonary vascular endothelial cells. J Biol Chem 277:5441–5447CrossRefPubMedGoogle Scholar
  32. 32.
    Tysnes BB, Larsen LF, Ness GO, Mahesparan R, Edvardsen K, Garcia-Cabrera I, Bjerkvig R (1996) Stimulation of glioma-cell migration by laminin and inhibition by anti-alpha3 and anti-beta1 integrin antibodies. Int J Cancer 67:777–784CrossRefPubMedGoogle Scholar
  33. 33.
    Watson JM, Harding TW, Golubovskaya V, Morris JS, Hunter D, Li X, Haskill JS, Earp HS (2001) Inhibition of the calcium-dependent tyrosine kinase (CADTK) blocks monocyte spreading and motility. J Biol Chem 276:3536–3542CrossRefPubMedGoogle Scholar
  34. 34.
    Zagzag D, Nomura M, Friedlander DR, Blanco CY, Gagner JP, Nomura N, Newcomb EW (2003) Geldanamycin inhibits migration of glioma cells in vitro: a potential role for hypoxia-inducible factor (HIF-1alpha) in glioma cell invasion. J Cell Physiol 196:394–402CrossRefPubMedGoogle Scholar
  35. 35.
    Zeng L, Si X, Yu WP, Le HT, Ng KP, Teng RM, Ryan K, Wang DZ, Ponniah S, Pallen CJ (2003) PTP alpha regulates integrin-stimulated FAK autophosphorylation and cytoskeletal rearrangement in cell spreading and migration. J Cell Biol 160:137–146CrossRefPubMedGoogle Scholar
  36. 36.
    Zheng C, Xing Z, Bian ZC, Guo C, Akbay A, Warner L, Guan JL (1998) Differential regulation of Pyk2 and focal adhesion kinase (FAK). The C-terminal domain of FAK confers response to cell adhesion. J Biol Chem 273:2384–2389PubMedGoogle Scholar
  37. 37.
    Zrihan-Licht S, Fu Y, Settleman J, Schinkmann K, Shaw L, Keydar I, Avraham S, Avraham H (2000) RAFTK/Pyk2 tyrosine kinase mediates the association of p190 RhoGAP with RasGAP and is involved in breast cancer cell invasion. Oncogene 19:1318–1328PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • A. Gutenberg
    • 1
  • W. Brück
    • 1
  • M. Buchfelder
    • 2
  • H. C. Ludwig
    • 2
  1. 1.Department of NeuropathologyGeorg August UniversityGöttingenGermany
  2. 2.Department of NeurosurgeryGeorg August UniversityGöttingenGermany

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