Regulation of Cell Adhesion Responses by Abl Family Kinases

  • Keith Quincy Tanis
  • Martin Alexander Schwartz
Part of the Molecular Biology Intelligence Unit book series (MBIU)


Integrins are cell surface receptors that mediate the interactions of cells with each other and the extracellular matrix. In this chapter, we review experiments indicating that the Abl family of nonreceptor tyrosine kinases, Abl and Arg in vertebrates, are important mediators of cellular responses to integrin engagement. During the early stages of cell spreading, integrins trigger the activation of Abl family kinases and their association with multiple focal adhesion proteins. These events lead to phosphorylation of several cytoskeletal regulatory proteins and changes in cell morphology and motility. Integrins may also utilize Abl family kinases to regulate nuclear processes such as gene expression, cell cycle progression and cell survival. Defects in the proper modulation of cell adhesive responses by Abl family kinases are thought to contribute to the progression of chronic myelogenous leukemia and could potentially underlie other human diseases and behavioral disorders.


Focal Adhesion Kinase Focal Adhesion Chronic Myelogenous Leukemia Integrin Receptor Integrin Signaling 
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  1. 1.
    Hynes RO. Integrins: versatility, modulation, and signaling in cell adhesion. Cell 1992; 69(1):11–25.PubMedCrossRefGoogle Scholar
  2. 2.
    Schwartz MA, Schaller MD, Ginsberg MH. Integrins: emerging paradigms of signal transduction. Annu Rev Cell Dev Biol 1995; 11:549–599.PubMedCrossRefGoogle Scholar
  3. 3.
    Giancotti FG, Ruoslahti E. Integrin signaling. Science 1999; 285(5430):1028–1032.PubMedCrossRefGoogle Scholar
  4. 4.
    Plow EF, Haas TA, Zhang L et al. Ligand binding to integrins. J Biol Chem 2000; 275(29):21785–21788.PubMedCrossRefGoogle Scholar
  5. 5.
    van der Flier A, Sonnenberg A. Function and interactions of integrins. Cell Tissue Res 2001; 305(3):285–298.PubMedCrossRefGoogle Scholar
  6. 6.
    Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell 2002; 110(6):673–687.PubMedCrossRefGoogle Scholar
  7. 7.
    Miranti CK, Brugge JS. Sensing the environment: a historical perspective on integrin signal transduction. Nat Cell Biol 2002; 4(4):E83–90.PubMedCrossRefGoogle Scholar
  8. 8.
    Zamir E, Geiger B. Molecular complexity and dynamics of cell-matrix adhesions. J Cell Sci 2001; 114 (Pt 20):3583–3590.PubMedGoogle Scholar
  9. 9.
    Schwartz MA, Ginsberg MH. Networks and crosstalk: integrin signalling spreads. Nat Cell Biol 2002; 4(4):E65–68.PubMedCrossRefGoogle Scholar
  10. 10.
    Nowell PC, Hungerford DA. Chromosome studies on normal and leukemic human leukocytes. J Natl Cancer Inst 1960; 25:85–109.PubMedGoogle Scholar
  11. 11.
    Rowley JD. Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973; 243(5405):290–293.PubMedCrossRefGoogle Scholar
  12. 12.
    Bartram CR, de Klein A, Hagemeijer A et al. Translocation of c-abl oncogene correlates with the presence of a Philadelphia chromosome in chronic myelocytic leukaemia. Nature 1983; 306(5940):277–280.PubMedCrossRefGoogle Scholar
  13. 13.
    Salesse S, Verfaillie CM. Mechanisms underlying abnormal trafficking and expansion of malignant progenitors in CML: BCR/ABL-induced defects in integrin function in CML. Oncogene 2002; 21(56):8605–8611.PubMedCrossRefGoogle Scholar
  14. 14.
    Wertheim JA, Miller JP, Xu L et al. The biology of chronic myelogenous leukemia: mouse models and cell adhesion. Oncogene 2002; 21(56):8612–8628.PubMedCrossRefGoogle Scholar
  15. 15.
    Gordon MY, Dowding CR, Riley GP et al. Altered adhesive interactions with marrow stroma of haematopoietic progenitor cells in chronic myeloid leukaemia. Nature 1987; 328(6128):342–344.PubMedCrossRefGoogle Scholar
  16. 16.
    Verfaillie CM, McCarthy JB, McGlave PB. Mechanisms underlying abnormal trafficking of malignant progenitors in chronic myelogenous leukemia. Decreased adhesion to stroma and fibronectin but increased adhesion to the basement membrane components laminin and collagen type IV. J Clin Invest 1992; 90(4):1232–1241.PubMedCrossRefGoogle Scholar
  17. 17.
    Bhatia R, Munthe HA, Verfaillie CM. Role of abnormal integrin-cytoskeletal interactions in impaired betal integrin function in chronic myelogenous leukemia hematopoietic progenitors. Exp Hematol 1999; 27(9):1384–1396.PubMedCrossRefGoogle Scholar
  18. 18.
    Ramaraj P, Singh H, Niu N et al. Effect of mutational inactivation of tyrosine kinase activity on BCR/ABL-induced abnormalities in cell growth and adhesion in human hematopoietic progenitors. Cancer Res 2004; 64(15):5322–5331.PubMedCrossRefGoogle Scholar
  19. 19.
    Bazzoni G, Carlesso N, Griffin JD et al. Bcr/Abl expression stimulates integrin function in hematopoietic cell lines. J Clin Invest 1996; 98(2):521–528.PubMedCrossRefGoogle Scholar
  20. 20.
    Kramer A, Homer S, Wilier A et al. Adhesion to fibronectin stimulates proliferation of wild-type and bcr/abl-transfected murine hematopoietic cells. Proc Natl Acad Sci USA 1999; 96(5):2087–2092.PubMedCrossRefGoogle Scholar
  21. 21.
    Wertheim JA, Forsythe K, Druker BJ et al. BCR-ABL-induced adhesion defects are tyrosine kinase-independent. Blood 2002; 99(11):4122–4130.PubMedCrossRefGoogle Scholar
  22. 22.
    Salgia R, Li JL, Ewaniuk DS et al. BCR/ABL induces multiple abnormalities of cytoskeletal function. J Clin Invest 1997; 100(1):46–57.PubMedCrossRefGoogle Scholar
  23. 23.
    Hurley RW, McCarthy JB, Verfaillie CM. Direct adhesion to bone marrow stroma via fibronectin receptors inhibits hematopoietic progenitor proliferation. J Clin Invest 1995; 96(1):511–519.PubMedCrossRefGoogle Scholar
  24. 24.
    Lundell BI, McCarthy JB, Kovach NL et al. Activation-dependent alpha5betal integrin-mediated adhesion to fibronectin decreases proliferation of chronic myelogenous leukemia progenitors and K562 cells. Blood 1996; 87(6):2450–2458.PubMedGoogle Scholar
  25. 25.
    Renshaw MW, McWhirter JR, Wang JY. The human leukemia oncogene bcr-abl abrogates the anchorage requirement but not the growth factor requirement for proliferation. Mol Cell Biol 1995; 15(3):1286–1293.PubMedGoogle Scholar
  26. 26.
    Oda T, Heaney C, Hagopian JR et al. Crkl is the major tyrosine-phosphorylated protein in neutrophils from patients with chronic myelogenous leukemia. J Biol Chem 1994; 269(37):22925–22928.PubMedGoogle Scholar
  27. 27.
    Gotoh A, Miyazawa K, Ohyashiki K et al. Tyrosine phosphorylation and activation of focal adhesion kinase (pl25FAK) by BCR-ABL oncoprotein. Exp Hematol 1995; 23(11):1153–1159.PubMedGoogle Scholar
  28. 28.
    Salgia R, Brunkhorst B, Pisick E et al. Increased tyrosine phosphorylation of focal adhesion proteins in myeloid cell lines expressing p210BCR/ABL. Oncogene 1995; 11(6):1149–1155.PubMedGoogle Scholar
  29. 29.
    Salgia R, Sattler M, Pisick E et al. p210BCR/ABL induces formation of complexes containing focal adhesion proteins and the protooncogene product pl20c-Cbl. Exp Hematol 1996; 24(2):310–313.PubMedGoogle Scholar
  30. 30.
    Salgia R, Pisick E, Sattler M et al. pl30CAS forms a signaling complex with the adapter protein CRKL in hematopoietic cells transformed by the BCR/ABL oncogene. J Biol Chem 1996; 271(41):25198–25203.PubMedCrossRefGoogle Scholar
  31. 31.
    Salgia R, Uemura N, Okuda K et al. CRKL links p210BCR/ABL with paxillin in chronic myelogenous leukemia cells. J Biol Chem 1995; 270(49):29145–29150.PubMedCrossRefGoogle Scholar
  32. 32.
    Wertheim JA, Perera SA, Hammer DA et al. Localization of BCR-ABL to F-actin regulates cell adhesion but does not attenuate CML development. Blood 2003; 102(6):2220–2228.PubMedCrossRefGoogle Scholar
  33. 33.
    McWhirter JR, Wang JY. Activation of tyrosinase kinase and microfilament-binding functions of c-abl by bcr sequences in bcr/abl fusion proteins. Mol Cell Biol 1991; 11(3):1553–1565.PubMedGoogle Scholar
  34. 34.
    McWhirter JR, Galasso DL, Wang JY. A coiled-coil oligomerization domain of Bcr is essential for the transforming function of Bcr-Abl oncoproteins. Mol Cell Biol 1993; 13(12):7587–7595.PubMedGoogle Scholar
  35. 35.
    Miller AL, Wang Y, Mooseker MS et al. The Abl-related gene (Arg) requires its F-actin-microtubule cross-linking activity to regulate lamellipodial dynamics during fibroblast adhesion. J Cell Biol 2004; 165(3):407–419.PubMedCrossRefGoogle Scholar
  36. 36.
    Woodring PJ, Meisenhelder J, Johnson SA et al. c-Abl phosphorylates Dok1 to promote filopodia during cell spreading. J Cell Biol 2004; 165(4):493–503.PubMedCrossRefGoogle Scholar
  37. 37.
    Woodring PJ, Litwack ED, O’Leary DD et al. Modulation of the F-actin cytoskeleton by c-Abl tyrosine kinase in cell spreading and neurite extension. J Cell Biol 2002; 156(5):879–892.PubMedCrossRefGoogle Scholar
  38. 38.
    Kain KH, Klemke RL. Inhibition of cell migration by Abl family tyrosine kinases through uncoupling of Crk-CAS complexes. J Biol Chem 2001; 276(19):16185–16192.PubMedCrossRefGoogle Scholar
  39. 39.
    Frasca F, Vigneri P, Vella V et al. Tyrosine kinase inhibitor STI571 enhances thyroid cancer cell motile response to Hepatocyte Growth Factor. Oncogene 2001; 20(29):3845–3856.PubMedCrossRefGoogle Scholar
  40. 40.
    Feller SM, Knudsen B, Hanafusa H. c-Abl kinase regulates the protein binding activity of c-Crk. EMBO J 1994; 13(10):2341–2351.PubMedGoogle Scholar
  41. 41.
    Van Etten RA, Jackson P, Baltimore D. The mouse type IV c-abl gene product is a nuclear protein, and activation of transforming ability is associated with cytoplasmic localization. Cell 1989; 58(4):669–678.PubMedCrossRefGoogle Scholar
  42. 42.
    Lewis JM, Baskaran R, Taagepera S et al. Integrin regulation of c-Abl tyrosine kinase activity and cytoplasmic-nuclear transport. Proc Natl Acad Sci USA 1996; 93(26):15174–15179.PubMedCrossRefGoogle Scholar
  43. 43.
    Wang B, Mysliwiec T, Krainc D et al. Identification of ArgBPl, an Arg protein tyrosine kinase binding protein that is the human homologue of a CNS-specific Xenopus gene. Oncogene 1996; 12(9):1921–1929.PubMedGoogle Scholar
  44. 44.
    Wang Y, Miller AL, Mooseker MS et al. The Abl-related gene (Arg) nonreceptor tyrosine kinase uses two F-actin-binding domains to bundle F-actin. Proc Natl Acad Sci USA 2001; 98(26):14865–14870.PubMedCrossRefGoogle Scholar
  45. 45.
    Van Etten RA. Cycling, stressed-out and nervous: cellular functions of c-Abl. Trends Cell Biol 1999; 9(5):179–186.PubMedCrossRefGoogle Scholar
  46. 46.
    Pendergast AM. The Abl family kinases: mechanisms of regulation and signaling. Adv Cancer Res 2002; 85:51–100.PubMedGoogle Scholar
  47. 47.
    Truong T, Sun G, Doorly M et al. Modulation of DNA damage-induced apoptosis by cell adhesion is independently mediated by p53 and c-Abl. Proc Natl Acad Sci USA 2003; 100(18):10281–10286.PubMedCrossRefGoogle Scholar
  48. 48.
    Hernandez SE, Settleman J, Koleske AJ. Adhesion-dependent regulation of pl90RhoGAP in the developing brain by the Abl-related gene tyrosine kinase. Curr Biol 2004; 14(8):691–696.PubMedCrossRefGoogle Scholar
  49. 49.
    Woodring PJ, Hunter T, Wang JY. Inhibition of c-Abl tyrosine kinase activity by filamentous actin. J Biol Chem 2001; 276(29):27104–27110.PubMedCrossRefGoogle Scholar
  50. 50.
    Lewis JM, Schwartz MA. Integrins regulate the association and phosphorylation of paxillin by c-Abl. J Biol Chem 1998; 273(23):14225–14230.PubMedCrossRefGoogle Scholar
  51. 51.
    Brasher BB, Van Etten RA. c-Abl has high intrinsic tyrosine kinase activity that is stimulated by mutation of the Src homology 3 domain and by autophosphorylation at two distinct regulatory tyrosines. J Biol Chem 2000; 275(45):35631–35637.PubMedCrossRefGoogle Scholar
  52. 52.
    Tanis KQ, Veach D, Duewel HS et al. Two distinct phosphorylation pathways have additive effects on Abl family kinase activation. Mol Cell Biol 2003; 23(11):3884–3896.PubMedCrossRefGoogle Scholar
  53. 53.
    Parsons JT. Focal adhesion kinase: the first ten years. J Cell Sci 2003; H6 (Pt 8):1409–1416.CrossRefGoogle Scholar
  54. 54.
    Cary LA, Guan JL. Focal adhesion kinase in integrin-mediated signaling. Front Biosci 1999; 4:D102–113.PubMedCrossRefGoogle Scholar
  55. 55.
    Plattner R, Kadlec L, DeMali KA et al. c-Abl is activated by growth factors and Src family kinases and has a role in the cellular response to PDGF. Genes Dev 1999; 13(18):2400–2411.PubMedCrossRefGoogle Scholar
  56. 56.
    Plattner R, Koleske AJ, Kazlauskas A et al. Bidirectional signaling links the Abelson kinases to the platelet-derived growth factor receptor. Mol Cell Biol 2004; 24(6):2573–2583.PubMedCrossRefGoogle Scholar
  57. 57.
    Zhang X, Chattopadhyay A, Ji QS et al. Focal adhesion kinase promotes phospholipase C-gammal activity. Proc Natl Acad Sci USA 1999; 96(16):9021–9026.PubMedCrossRefGoogle Scholar
  58. 58.
    Plattner R, Irvin BJ, Guo S et al. A new link between the c-Abl tyrosine kinase and phosphoinositide signalling through PLC-gammal. Nat Cell Biol 2003; 5(4):309–319.PubMedCrossRefGoogle Scholar
  59. 59.
    Clegg DO, Wingerd KL, Hikita ST et al. Integrins in the development, function and dysfunction of the nervous system. Front Biosci 2003; 8:d723–750.PubMedCrossRefGoogle Scholar
  60. 60.
    Schaller MD. Paxillin: a focal adhesion-associated adaptor protein. Oncogene 2001; 20(44):6459–6472.PubMedCrossRefGoogle Scholar
  61. 61.
    Brown MC, Turner CE. Paxillin: adapting to change. Physiol Rev 2004; 84(4):1315–1339.PubMedCrossRefGoogle Scholar
  62. 62.
    Kwiatkowski AV, Gertler FB, Loureiro JJ. Function and regulation of Ena/VASP proteins. Trends Cell Biol 2003; 13(7):386–392.PubMedCrossRefGoogle Scholar
  63. 63.
    Howe AK, Hogan BP, Juliano RL. Regulation of vasodilator-stimulated phosphoprotein phospho-rylation and interaction with Abl by protein kinase A and cell adhesion. J Biol Chem 2002; 277(41):38121–38126.PubMedCrossRefGoogle Scholar
  64. 64.
    Renshaw MW, Lewis JM, Schwartz MA. The c-Abl tyrosine kinase contributes to the transient activation of MAP kinase in cells plated on fibronectin. Oncogene 2000; 19(28):3216–3219.PubMedCrossRefGoogle Scholar
  65. 65.
    Assoian RK, Schwartz MA. Coordinate signaling by integrins and receptor tyrosine kinases in the regulation of G1 phase cell-cycle progression. Curr Opin Genet Dev 2001; 11(1):48–53.PubMedCrossRefGoogle Scholar
  66. 66.
    Juliano RL, Reddig P, Alahari S et al. Integrin regulation of cell signalling and motility. Biochem Soc Trans 2004; 32 (Pt3):443–446.PubMedCrossRefGoogle Scholar
  67. 67.
    Slack-Davis JK, Parsons JT. Emerging views of integrin signaling: implications for prostate cancer. J Cell Biochem 2004; 91(1):41–46.PubMedCrossRefGoogle Scholar
  68. 68.
    Sini P, Cannas A, Koleske AJ et al. Abl-dependent tyrosine phosphorylation of Sos-1 mediates growth-factor-induced Rac activation. Nat Cell Biol 2004; 6(3):268–274.PubMedCrossRefGoogle Scholar
  69. 69.
    Wisniewski D, Strife A, Wojciechowicz D et al. A 62-kilodalton tyrosine phosphoprotein constitutively present in primary chronic phase chronic myelogenous leukemia enriched lineage negative blast populations. Leukemia 1994; 8(4):688–693.PubMedGoogle Scholar
  70. 70.
    Carpino N, Wisniewski D, Strife A et al. p62(dok): a constitutively tyrosine-phosphorylated, GAP-associated protein in chronic myelogenous leukemia progenitor cells. Cell 1997; 88(2):197–204.PubMedCrossRefGoogle Scholar
  71. 71.
    Yamanashi Y, Baltimore D. Identification of the Abl-and rasGAP-associated 62 kDa protein as a docking protein, Dok. Cell 1997; 88(2):205–211.PubMedCrossRefGoogle Scholar
  72. 72.
    Campellone KG, Rankin S, Pawson T et al. Clustering of Nck by a 12-residue Tir phosphopeptide is sufficient to trigger localized actin assembly. J Cell Biol 2004; 164(3):407–416.PubMedCrossRefGoogle Scholar
  73. 73.
    Rivera GM, Briceno CA, Takeshima F et al. Inducible clustering of membrane-targeted SH3 domains of the adaptor protein Nck triggers localized actin polymerization. Curr Biol 2004; 14(1):11–22.PubMedCrossRefGoogle Scholar
  74. 74.
    Ridley AJ, Hall A. The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell 1992; 70(3):389–399.PubMedCrossRefGoogle Scholar
  75. 75.
    Arthur WT, Noren NK, Burridge K. Regulation of Rho family GTPases by cell-cell and cell-matrix adhesion. Biol Res 2002; 35(2):239–246.PubMedCrossRefGoogle Scholar
  76. 76.
    Arthur WT, Petch LA, Burridge K. Integrin engagement suppresses RhoA activity via a c-Src-de-pendent mechanism. Curr Biol 2000; 10(12):719–722.PubMedCrossRefGoogle Scholar
  77. 77.
    Ren XD, Kiosses WB, Sieg DJ et al. Focal adhesion kinase suppresses Rho activity to promote focal adhesion turnover. J Cell Sci 2000; 113 (Pt 20):3673–3678.PubMedGoogle Scholar
  78. 78.
    Schaller MD, Parsons JT. pp 125FAK-dependent tyrosine phosphorylation of paxillin creates a high-affinity binding site for Crk. Mol Cell Biol 1995; 15(5):2635–2645.PubMedGoogle Scholar
  79. 79.
    Lin YH, Park ZY, Lin D et al. Regulation of cell migration and survival by focal adhesion targeting of Lasp-1. J Cell Biol 2004; 165(3):421–432.PubMedCrossRefGoogle Scholar
  80. 80.
    Tybulewicz VL, Crawford CE, Jackson PK et al. Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene. Cell 1991; 65(7):1153–1163.PubMedCrossRefGoogle Scholar
  81. 81.
    Li B, Boast S, de los Santos K et al. Mice deficient in Abl are osteoporotic and have defects in osteoblast maturation. Nat Genet 2000; 24(3):304–308.PubMedCrossRefGoogle Scholar
  82. 82.
    Koleske AJ, Gifford AM, Scott ML et al. Essential roles for the Abl and Arg tyrosine kinases in neurulation. Neuron 1998; 21(6):1259–1272.PubMedCrossRefGoogle Scholar
  83. 83.
    D’Sa C, Duman RS. Antidepressants and neuroplasticity. Bipolar Disord 2002; 4(3):183–194.PubMedCrossRefGoogle Scholar
  84. 84.
    Quiroz JA, Singh J, Gould TD et al. Emerging experimental therapeutics for bipolar disorder: clues from the molecular pathophysiology. Mol Psychiatry 2004; 9(8):756–76.PubMedCrossRefGoogle Scholar
  85. 85.
    Kaufmann WE, Moser HW. Dendritic anomalies in disorders associated with mental retardation. Cereb Cortex 2000; 10(10):981–991.PubMedCrossRefGoogle Scholar
  86. 86.
    Moresco EYM, Donaldson S, Williamson A et al. Intergrin-mediated dendrite branch maintenance requires Abelson (Abl) family kinase. J Neurosci 20004; 25(26):6105–6118.Google Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2006

Authors and Affiliations

  • Keith Quincy Tanis
    • 1
  • Martin Alexander Schwartz
    • 2
  1. 1.Department of Psychiatry, Laboratory of Molecular PsychiatryYale UniversityNew HavenUSA
  2. 2.Department of MicrobiologyUniversity of VirginiaCharlottesvilleUSA

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