Skip to main content
Log in

Integrin Signaling and Mammary Cell Function

  • Published:
Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

The mammary gland is a highly organized tissue, containing ductal structures, secretory alveolar units, and a supporting stroma. The organization of the epithelial cells within the tissue depends upon cell–cell adhesion as well as cell interactions with the extracellular matrix that underlies the epithelial units and makes up most of the organization of the stroma. Adhesion to the extracellular matrix is mediated by a class of heterodimeric transmembrane receptors called integrins, which cluster at focal adhesions. Integrins link the matrix with an intracellular structural scaffold, the cytoskeleton, as well as with signaling enzymes that direct cell survival, proliferation, differentiation, and migration. Two key enzymes that are recruited to sites of integrin clustering are focal adhesion kinase and integrin-linked kinase. Both enzymes are involved with communication downstream of integrins and have key roles in regulating cell behavior. This review will focus on what is known about focal adhesion kinase and integrin-linked kinase signaling and will discuss current evidence about their role in mammary gland biology and neoplasia.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. R. O. Hynes (2002). Integrins: Bidirectional, allosteric signaling machines. Cell 110: 673–687.

    Google Scholar 

  2. A. Howe, A. E. Aplin, S. K. Alahari, and R. L. Juliano (1998). Integrin signaling and cell growth control. Curr. Opin. Cell Biol. 10: 220–231.

    Google Scholar 

  3. B. Geiger, A. Bershadsky, R. Pankov, and K. M. Yamada (2001). Transmembrane crosstalk between the extracellular matrix—cytoskeleton crosstalk. Nat. Rev. Mol. Cell Biol. 2: 793–805.

    Google Scholar 

  4. B. Geiger and A. Bershadsky (2002). Exploring the neighborhood: Adhesion-coupled cell mechanosensors. Cell 110: 139–142.

    Google Scholar 

  5. C. Bokel and N. H. Brown (2002). Integrins in development: Moving on, responding to, and sticking to the extracellular matrix. Dev. Cell 3: 311–321.

    Google Scholar 

  6. D. Medina (1996). The mammary gland: A unique organ for the study of development and tumorigenesis. J. Mamm. Gland Biol. Neoplasia 1: 5–19.

    Google Scholar 

  7. T. C. Klinowska, J. V. Soriano, G. M. Edwards, J. M. Oliver, A. J. Valentijn, R. Montesano, and C. H. Streuli (1999). Laminin and beta1 integrins are crucial for normal mammary gland development in the mouse. Dev. Biol. 215: 13–32.

    Google Scholar 

  8. N. Farrelly, Y. J. Lee, J. Oliver, C. Dive, and C. H. Streuli (1999). Extracellular matrix regulates apoptosis in mammary epithelium through a control on insulin signaling. J. Cell Biol. 144: 1337–1348.

    Google Scholar 

  9. S. Pullan, J. Wilson, A. Metcalfe, G. M. Edwards, N. Goberdhan, J. Tilly, J. A. Hickman, C. Dive, and C. H. Streuli (1996). Requirement of basement membrane for the suppression of programmed cell death in mammary epithelium. J. Cell Sci. 109: 631–642.

    Google Scholar 

  10. C. H. Streuli and M. J. Bissell (1990). Expression of extracellular matrix components is regulated by substratum. J. Cell Biol. 110: 1405–1415.

    Google Scholar 

  11. E. Y. Lee, G. Parry, and M. J. Bissell (1984). Modulation of secreted proteins of mouse mammary epithelial cells by the collagenous substrata. J. Cell Biol. 98: 146–155.

    Google Scholar 

  12. J. Aggeler, J. Ward, L. M. Blackie, M. H. Barcellos-Hoff, C. H. Streuli, and M. J. Bissell (1991). Cytodifferentiation of mouse mammary epithelial cells cultured on a reconstituted basement membrane reveals striking similarities to development in vivo. J. Cell Sci. 99: 407–417.

    Google Scholar 

  13. C. H. Streuli, C. Schmidhauser, N. Bailey, P. Yurchenco, A. P. Skubitz, C. Roskelley, and M. J. Bissell (1995). Laminin mediates tissue-specific gene expression in mammary epithelia. J. Cell Biol. 129: 591–603.

    Google Scholar 

  14. M. H. Barcellos-Hoff, J. Aggeler, T. G. Ram, and M. J. Bissell (1989). Functional differentiation and alveolar morphogenesis of primary mammary cultures on reconstituted basement membrane. Development 105: 223–235.

    Google Scholar 

  15. M. L. Li, J. Aggeler, D. A. Farson, C. Hatier, J. Hassell, and M. J. Bissell (1987). Influence of a reconstituted basement membrane and its components on casein gene expression and secretion in mouse mammary epithelial cells. Proc. Natl. Acad. Sci. U.S.A. 84: 136–140.

    Google Scholar 

  16. M. M. Faraldo, M. A. Deugnier, S. Tlouzeau, J. P. Thiery, and M. A. Glukhova (2002). Perturbation of beta1-integrin function in involuting mammary gland results in premature dedifferentiation of secretory epithelial cells. Mol. Biol. Cell 13: 3521–3531.

    Google Scholar 

  17. C. H. Streuli, N. Bailey, and M. J. Bissell (1991). Control of mammary epithelial differentiation: Basement membrane induces tissue-specific gene expression in the absence of cell-cell interaction and morphological polarity. J. Cell Biol. 115: 1383–1395.

    Google Scholar 

  18. C. H. Damsky and D. Ilic (2002). Integrin signaling: It's where the action is. Curr. Opin. Cell Biol. 14: 594–602.

    Google Scholar 

  19. D. R. Critchley (2000). Focal adhesions—The cytoskeletal connection. Curr. Opin. Cell Biol. 12: 133–139.

    Google Scholar 

  20. C. Brakebusch and R. Fassler (2003). The integrin-actin connection, an eternal love affair. EMBO J. 22: 2324–2333.

    Google Scholar 

  21. E. Cukierman, R. Pankov, and K. M. Yamada (2002). Cell interactions with three-dimensional matrices. Curr. Opin. Cell Biol. 14: 633–639.

    Google Scholar 

  22. D. Ilic, Y. Furuta, S. Kanazawa, N. Takeda, K. Sobue, N. Nakatsuji, S. Nomura, J. Fujimoto, M. Okada, and T. Yamamoto (1995). Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice. Nature 377: 539–544.

    Google Scholar 

  23. T. Sakai, S. Li, D. Docheva, C. Grashoff, K. Sakai, G. Kostka, A. Braun, A. Pfeifer, P. D. Yurchenco, and R. Fassler (2003). Integrin-linked kinase (ILK) is required for polarizing the epiblast, cell adhesion, and controlling actin accumulation. Genes Dev. 17: 926–940.

    Google Scholar 

  24. M. D. Schaller, C. A. Borgman, B. S. Cobb, R. R. Vines, A. B. Reynolds, and J. T. Parsons (1992). pp125FAK a structurally distinctive protein-tyrosine kinase associated with focal adhesions. Proc. Natl. Acad. Sci. U.S.A. 89: 5192–5196.

    Google Scholar 

  25. D. D. Schlaepfer, C. R. Hauck, and D. J. Sieg (1999). Signaling through focal adhesion kinase. Prog. Biophys. Mol. Biol. 71: 435–478.

    Google Scholar 

  26. C. R. Hauck, D. A. Hsia, and D. D. Schlaepfer (2002). The focal adhesion kinase—a regulator of cell migration and invasion. IUBMB Life 53: 115–119.

    Google Scholar 

  27. E. L. George, E. N. Georges-Labouesse, R. S. Patel-King, H. Rayburn, and R. O. Hynes (1993). Defects in mesoderm, neural tube and vascular development in mouse embryos lacking fibronectin. Development 119: 1079–1091.

    Google Scholar 

  28. M. D. Schaller and J. T. Parsons (1995). pp125FAK-dependent tyrosine phosphorylation of paxillin creates a high-affinity binding site for Crk. Mol. Cell Biol. 15: 2635–2645.

    Google Scholar 

  29. J. A. Girault, G. Labesse, J. P. Mornon, and I. Callebaut (1999). The N-termini of FAK and JAKs contain divergent band 4.1 domains. Trends Biochem. Sci. 24: 54–57.

    Google Scholar 

  30. R. Chen, O. Kim, M. Li, X. Xiong, J. L. Guan, H. J. Kung, H. Chen, Y. Shimizu, and Y. Qiu (2001). Regulation of the PH-domain-containing tyrosine kinase Etk by focal adhesion kinase through the FERM domain. Nat. Cell Biol. 3: 439–444.

    Google Scholar 

  31. S. K. Hanks and T. R. Polte (1997). Signaling through focal adhesion kinase. Bioessays 19: 137–145.

    Google Scholar 

  32. H. C. Chen and J. L. Guan (1994). Stimulation of phosphatidylinositol 3'-kinase association with focal adhesion kinase by platelet-derived growth factor. J. Biol. Chem. 269: 31229–31233.

    Google Scholar 

  33. T. F. Franke, D. R. Kaplan, L. C. Cantley, and A. Toker (1997). Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate. Science 275: 665–668.

    Google Scholar 

  34. D. R. Alessi, S. R. James, C. P. Downes, A. B. Holmes, P. R. Gaffney, C. B. Reese, and P. Cohen (1997). Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr. Biol. 7: 261–269.

    Google Scholar 

  35. L. del Peso, M. Gonzalez-Garcia, C. Page, R. Herrera, and G. Nunez (1997). Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 278: 687–689.

    Google Scholar 

  36. H. Yamaguchi and H. G. Wang (2001). The protein kinase PKB/Akt regulates cell survival and apoptosis by inhibiting Bax conformational change. Oncogene 20: 7779–7786.

    Google Scholar 

  37. F. Tsuruta, N. Masuyama, and Y. Gotoh (2002). The phosphatidylinositol 3-kinase (PI3K)-Akt pathway suppresses Bax translocation to mitochondria. J. Biol. Chem. 277: 14040–14047.

    Google Scholar 

  38. D. D. Schlaepfer and T. Hunter (1997). Focal adhesion kinase overexpression enhances ras-dependent integrin signaling to ERK2/mitogen-activated protein kinase through interactions with and activation of c-Src. J. Biol. Chem. 272: 13189–13195.

    Google Scholar 

  39. S. M. Frisch, K. Vuori, E. Ruoslahti, and P. Y. Chan-Hui (1996). Control of adhesion-dependent cell survival by focal adhesion kinase. J. Cell Biol. 134: 793–799.

    Google Scholar 

  40. T. H. Lin, A. E. Aplin, Y. Shen, Q. Chen, M. Schaller, L. Romer, I. Aukhil, and R. L. Juliano (1997). Integrin-mediated activation of MAP kinase is independent of FAK: Evidence for dual integrin signaling pathways in fibroblasts. J. Cell Biol. 136: 1385–1395.

    Google Scholar 

  41. K. K. Wary, F. Mainiero, S. J. Isakoff, E. E. Marcantonio, and F. G. Giancotti (1996). The adaptor protein Shc couples a class of integrins to the control of cell cycle progression. Cell, 87: 733–743.

    Google Scholar 

  42. Q. Q. Pu and C. H. Streuli (2002). Integrin control of cell cycle: A new role for ubiquitin ligase. Bioessays 24: 17–21.

    Google Scholar 

  43. E. A. Almeida, D. Ilic, Q. Han, C. R. Hauck, F. Jin, H. Kawakatsu, D. D. Schlaepfer, and C. H. Damsky (2000). Matrix survival signaling: From fibronectin via focal adhesion kinase to c-Jun NH(2)-terminal kinase. J. Cell Biol. 149: 741–754.

    Google Scholar 

  44. O. Kim, J. Yang, and Y. Qiu (2002). Selective activation of small GTPase RhoA by tyrosine kinase Etk through its pleckstrin homology domain. J. Biol. Chem. 277: 30066–30071.

    Google Scholar 

  45. F. Aoudjit and K. Vuori (2001). Matrix attachment regulates Fas-induced apoptosis in endothelial cells: A role for c-flip and implications for anoikis. J. Cell Biol. 152: 633–643.

    Google Scholar 

  46. N. Boudreau, C. J. Sympson, Z. Werb, and M. J. Bissell (1995). Suppression of ICE and apoptosis in mammary epithelial cells by extracellular matrix. Science 267: 891–893.

    Google Scholar 

  47. S. M. Frisch and H. Francis (1994). Disruption of epithelial cell-matrix interactions induces apoptosis. J. Cell Biol. 124: 619–626.

    Google Scholar 

  48. A. P. Gilmore, A. D. Metcalfe, L. H. Romer, and C. H. Streuli (2000). Integrin-mediated survival signals regulate the apoptotic function of Bax through its conformation and subcellular localization. J. Cell Biol. 149: 431–446.

    Google Scholar 

  49. A. Khwaja, P. Rodriguez-Viciana, S. Wennstrom, P. H. Warne, and J. Downward (1997). Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway. EMBO. J. 16: 2783–2793.

    Google Scholar 

  50. J. E. MeredithJr., B. Fazeli, and M. A. Schwartz (1993). The extracellular matrix as a cell survival factor. Mol. Biol. Cell 4: 953–961.

    Google Scholar 

  51. J. E. Hungerford, M. T. Compton, M. L. Matter, B. G. Hoffstrom, and C. A. Otey (1996). Inhibition of pp125FAK in cultured fibroblasts results in apoptosis. J. Cell Biol. 135: 1383–1390.

    Google Scholar 

  52. A. P. Gilmore and L. H. Romer (1996). Inhibition of focal adhesion kinase (FAK) signaling in focal adhesions decreases cell motility and proliferation. Mol. Biol. Cell 7: 1209–1224.

    Google Scholar 

  53. K. Nolan, J. Lacoste, and J. T. Parsons (1999). Regulated expression of focal adhesion kinase-related nonkinase, the autonomously expressed C-terminal domain of focal adhesion kinase. Mol. Cell Biol. 19: 6120–6129.

    Google Scholar 

  54. P. Wang, A. J. Valentijn, A. P. Gilmore, and C. H. Streuli (2003). Early events in the anoikis program occur in the absence of caspase activation. J. Biol. Chem. 278: 19917–19925.

    Google Scholar 

  55. A. J. Valentijn, A. D. Metcalfe, J. Kott, C. H. Streuli, and A. P. Gilmore (2003). Spatial and temporal changes in Bax subcellular localization during anoikis. J. Cell Biol. 162: 599–612.

    Google Scholar 

  56. D. Ilic, E. A. Almeida, D. D. Schlaepfer, P. Dazin, S. Aizawa, and C. H. Damsky (1998). Extracellular matrix survival signals transduced by focal adhesion kinase suppress p53-mediated apoptosis. J. Cell Biol. 143: 547–560.

    Google Scholar 

  57. K. A. Green and C. H. Streuli (2004). Apoptosis regulation in the mammary gland. Cell. Mol. Life Sci. (in press).

  58. A. D. Metcalfe, A. Gilmore, T. Klinowska, J. Oliver, A. J. Valentijn, R. Brown, A. Ross, G. MacGregor, J. A. Hickman, and C. H. Streuli (1999). Developmental regulation of Bcl-2 family protein expression in the involuting mammary gland. J. Cell Sci. 112: 1771–1783.

    Google Scholar 

  59. J. M. Prince, T. C. Klinowska, E. Marshman, E. T. Lowe, U. Mayer, J. Miner, D. Aberdam, D. Vestweber, B. Gusterson, and C. H. Streuli (2002). Cell-matrix interactions during development and apoptosis of the mouse mammary gland in vivo. Dev. Dyn. 223: 497–516.

    Google Scholar 

  60. M. M. Faraldo, M. A. Deugnier, M. Lukashev, J. P. Thiery, and M. A. Glukhova (1998). Perturbation of beta1-integrin function alters the development of murine mammary gland. EMBO J. 17: 2139–2147.

    Google Scholar 

  61. M. M. Faraldo, M. A. Deugnier, J. P. Thiery, and M. A. Glukhova (2001). Growth defects induced by perturbation of beta1-integrin function in the mammary gland epithelium result from a lack of MAPK activation via the Shc and Akt pathways. EMBO Rep. 2: 431–437.

    Google Scholar 

  62. L. V. Owens, L. Xu, R. J. Craven, G. A. Dent, T. M. Weiner, L. Kornberg, E. T. Liu, and W. G. Cance (1995). Overexpression of the focal adhesion kinase (p125FAK) in invasive human tumors. Cancer Res. 55: 2752–2755.

    Google Scholar 

  63. T. M. Weiner, E. T. Liu, R. J. Craven, and W. G. Cance (1993). Expression of focal adhesion kinase gene and invasive cancer. Lancet 342: 1024–1025.

    Google Scholar 

  64. L. J. Kornberg (1998). Focal adhesion kinase expression in oral cancers. Head Neck 20: 634–639.

    Google Scholar 

  65. G. B. Schneider, Z. Kurago, R. Zaharias, L. M. Gruman, M. D. Schaller, and M. J. Hendrix (2002). Elevated focal adhesion kinase expression facilitates oral tumor cell invasion. Cancer 95: 2508–2515.

    Google Scholar 

  66. P. L. Judson, X. He, W. G. Cance, and L. Van Le (1999). Overexpression of focal adhesion kinase, a protein tyrosine kinase, in ovarian carcinoma. Cancer 86: 1551–1556.

    Google Scholar 

  67. L. Tremblay, W. Hauck, A. G. Aprikian, L. R. Begin, A. Chapdelaine, and S. Chevalier (1996). Focal adhesion kinase (pp125FAK) expression, activation and association with paxillin and p50CSK in human metastatic prostate carcinoma. Int. J. Cancer 68: 164–171.

    Google Scholar 

  68. D. Wang, J. R. Grammer, C. S. Cobbs, J. E. StewartJr., Z. Liu, R. Rhoden, T. P. Hecker, Q. Ding, and C. L. Gladson (2000). p125 focal adhesion kinase promotes malignant astrocytoma cell proliferation in vivo. J. Cell Sci. 113(Pt. 23): 4221–4230.

    Google Scholar 

  69. S. J. McCormack, S. E. Brazinski, J. L. MooreJr., B. A. Werness, and D. J. Goldstein (1997). Activation of the focal adhesion kinase signal transduction pathway in cervical carcinoma cell lines and human genital epithelial cells immortalized with human papillomavirus type 18. Oncogene 15: 265–274.

    Google Scholar 

  70. T. Akasaka, R. L. van Leeuwen, I. G. Yoshinaga, M. C. MihmJr., and H. R. Byers (1995). Focal adhesion kinase (p125FAK) expression correlates with motility of human melanoma cell lines. J. Invest. Dermatol. 105: 104–108.

    Google Scholar 

  71. M. Agochiya, V. G. Brunton, D. W. Owens, E. K. Parkinson, C. Paraskeva, W. N. Keith, and M. C. Frame (1999). Increased dosage and amplification of the focal adhesion kinase gene in human cancer cells. Oncogene 18: 5646–5653.

    Google Scholar 

  72. O. Kahana, M. Micksche, I. P. Witz, and I. Yron (2002). The focal adhesion kinase (P125FAK) is constitutively active in human malignant melanoma. Oncogene 21: 3969–3977.

    Google Scholar 

  73. M. Glukhova, V. Koteliansky, X. Sastre, and J. P. Thiery (1995). Adhesion systems in normal breast and in invasive breast carcinoma. Am. J. Pathol. 146: 706–716.

    Google Scholar 

  74. W. G. Cance, J. E. Harris, M. V. Iacocca, E. Roche, X. Yang, J. Chang, S. Simkins, and L. Xu (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: 2417–2423.

    Google Scholar 

  75. L. H. Xu, X. Yang, R. J. Craven, and W. G. Cance (1998). The COOH-terminal domain of the focal adhesion kinase induces loss of adhesion and cell death in human tumor cells. Cell Growth Differ. 9: 999–1005.

    Google Scholar 

  76. L. H. Xu, L. V. Owens, G. C. Sturge, X. Yang, E. T. Liu, R. J. Craven, and W. G. Cance (1996). Attenuation of the expression of the focal adhesion kinase induces apoptosis in tumor cells. Cell Growth Differ. 7: 413–418.

    Google Scholar 

  77. L. Beviglia, V. Golubovskaya, L. Xu, X. Yang, R. J. Craven, and W. G. Cance (2003). Focal adhesion kinase N-terminus in breast carcinoma cells induces rounding, detachment and apoptosis. Biochem. J. 373: 201–210.

    Google Scholar 

  78. L. H. Xu, X. Yang, C. A. Bradham, D. A. Brenner, A. S. BaldwinJr., R. J. Craven, and W. G. Cance (2000). The focal adhesion kinase suppresses transformation-associated, anchorage-independent apoptosis in human breast cancer cells. Involvement of death receptor-related signaling pathways. J. Biol. Chem. 275: 30597–30604.

    Google Scholar 

  79. V. Golubovskaya, L. Beviglia, L. H. Xu, H. S. EarpIII, R. Craven, and W. Cance (2002). Dual inhibition of focal adhesion kinase and epidermal growth factor receptor pathways cooperatively induces death receptor-mediated apoptosis in human breast cancer cells. J. Biol. Chem. 277: 38978–38987.

    Google Scholar 

  80. Z. Lu, G. Jiang, P. Blume-Jensen, and T. Hunter (2001). Epidermal growth factor-induced tumor cell invasion and metastasis initiated by dephosphorylation and downregulation of focal adhesion kinase. Mol. Cell Biol. 21: 4016–4031.

    Google Scholar 

  81. D. J. Sieg, C. R. Hauck, and D. D. Schlaepfer (1999). Required role of focal adhesion kinase (FAK) for integrin-stimulated cell migration. J. Cell Sci. 112(Pt. 16): 2677–2691.

    Google Scholar 

  82. G. E. Hannigan, C. Leung-Hagesteijn, L. Fitz-Gibbon, M. G. Coppolino, G. Radeva, J. Filmus, J. C. Bell, and S. Dedhar (1996). Regulation of cell adhesion and anchorage-dependent growth by a new beta 1-integrin-linked protein kinase. Nature 379: 91–96.

    Google Scholar 

  83. F. Li, Y. Zhang, and C. Wu (1999). Integrin-linked kinase is localized to cell-matrix focal adhesions but not cell-cell adhesion sites and the focal adhesion localization of integrin-linked kinase is regulated by the PINCH-binding ANK repeats. J. Cell Sci. 112: 4589–4599.

    Google Scholar 

  84. C. Wu and S. Dedhar (2001). Integrin-linked kinase (ILK) and its interactors: A new paradigm for the coupling of extracellular matrix to actin cytoskeleton and signaling complexes. J. Cell Biol. 155: 505–510.

    Google Scholar 

  85. S. Dedhar (2000). Cell-substrate interactions and signaling through ILK. Curr. Opin. Cell Biol. 12: 250–256.

    Google Scholar 

  86. M. Delcommenne, C. Tan, V. Gray, L. Rue, J. Woodgett, and S. Dedhar (1998). Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. Proc. Natl. Acad. Sci. U.S.A. 95: 11211–11216.

    Google Scholar 

  87. A. M. Morimoto, M. G. Tomlinson, K. Nakatani, J. B. Bolen, R. A. Roth, and R. Herbst (2000). The MMAC1 tumor suppressor phosphatase inhibits phospholipase C and integrin-linked kinase activity. Oncogene 19: 200–209.

    Google Scholar 

  88. C. Leung-Hagesteijn, A. Mahendra, I. Naruszewicz, and G. E. Hannigan (2001). Modulation of integrin signal transduction by ILKAP, a protein phosphatase 2C associating with the integrin-linked kinase, ILK1. EMBO. J. 20: 2160–2170.

    Google Scholar 

  89. D. K. Lynch, C. A. Ellis, P. A. Edwards, and I. D. Hiles (1999). Integrin-linked kinase regulates phosphorylation of serine 473 of protein kinase B by an indirect mechanism. Oncogene 18: 8024–8032.

    Google Scholar 

  90. S. Persad, S. Attwell, V. Gray, N. Mawji, J. T. Deng, D. Leung, J. Yan, J. Sanghera, M. P. Walsh, and S. Dedhar (2001). Regulation of protein kinase B/Akt-serine 473 phosphorylation by integrin-linked kinase: Critical roles for kinase activity and amino acids arginine 211 and serine 343. J. Biol. Chem. 276: 27462–27469.

    Google Scholar 

  91. M. M. Hill, J. Feng, and B. A. Hemmings (2002). Identification of a plasma membrane Raft-associated PKB Ser473 kinase activity that is distinct from ILK and PDK1. Curr. Biol. 12: 1251–1255.

    Google Scholar 

  92. L. Zhuang, J. Lin, M. L. Lu, K. R. Solomon, and M. R. Freeman (2002). Cholesterol-rich lipid rafts mediate akt-regulated survival in prostate cancer cells. Cancer Res. 62: 2227–2231.

    Google Scholar 

  93. A. A. Troussard, N. M. Mawji, C. Ong, A. Mui, R. St-Arnaud, and S. Dedhar (2003). Conditional knock-out of integrin-linked kinase demonstrates an essential role in protein kinase B/Akt activation. J. Biol. Chem. 278: 22374–22378.

    Google Scholar 

  94. L. Terpstra, J. Prud'homme, A. Arabian, S. Takeda, G. Karsenty, S. Dedhar, and R. St-Arnaud (2003). Reduced chondrocyte proliferation and chondrodysplasia in mice lacking the integrin-linked kinase in chondrocytes. J. Cell Biol. 162: 139–148.

    Google Scholar 

  95. I. Shin, F. M. Yakes, F. Rojo, N. Y. Shin, A. V. Bakin, J. Baselga, and C. L. Arteaga (2002). PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization. Nat. Med. 8: 1145–1152.

    Google Scholar 

  96. Y. Tu, F. Li, S. Goicoechea, and C. Wu (1999). The LIM-only protein PINCH directly interacts with integrin-linked kinase and is recruited to integrin-rich sites in spreading cells. Mol. Cell Biol. 19: 2425–2434.

    Google Scholar 

  97. Y. Tu, F. Li, and C. Wu (1998). Nck-2, a novel Src homology2/3-containing adaptor protein that interacts with the LIM-only protein PINCH and components of growth factor receptor kinase-signaling pathways. Mol. Biol. Cell 9: 3367–3382.

    Google Scholar 

  98. Y. Tu, Y. Huang, Y. Zhang, Y. Hua, and C. Wu (2001). A new focal adhesion protein that interacts with integrin-linked kinase and regulates cell adhesion and spreading. J. Cell Biol. 153: 585–598.

    Google Scholar 

  99. S. N. Nikolopoulos and C. E. Turner (2001). Integrin-linked kinase (ILK) binding to paxillin LD1 motif regulates ILK localization to focal adhesions. J. Biol. Chem. 276: 23499–23505.

    Google Scholar 

  100. S. N. Nikolopoulos and C. E. Turner (2002). Molecular dissection of actopaxin-integrin-linked kinase-Paxillin interactions and their role in subcellular localization. J. Biol. Chem. 277: 1568–1575.

    Google Scholar 

  101. Y. Zhang, K. Chen, Y. Tu, A. Velyvis, Y. Yang, J. Qin, and C. Wu (2002). Assembly of the PINCH-ILK-CH-ILKBP complex precedes and is essential for localization of each component to cell-matrix adhesion sites. J. Cell Sci. 115: 4777–4786.

    Google Scholar 

  102. I. Hayashi, K. Vuori, and R. C. Liddington (2002). The focal adhesion targeting (FAT) region of focal adhesion kinase is a four-helix bundle that binds paxillin. Nat. Struct. Biol. 9: 101–106.

    Google Scholar 

  103. T. Fukuda, L. Guo, X. Shi, and C. Wu (2003). CH-ILKBP regulates cell survival by facilitating the membrane translocation of protein kinase B/Akt. J. Cell Biol. 160: 1001–1008.

    Google Scholar 

  104. S. Yamaji, A. Suzuki, Y. Sugiyama, Y. Koide, M. Yoshida, H. Kanamori, H. Mohri, S. Ohno, and Y. Ishigatsubo (2001). A novel integrin-linked kinase-binding protein, affixin, is involved in the early stage of cell-substrate interaction. J. Cell Biol. 153: 1251–1264.

    Google Scholar 

  105. G. Rosenberger, I. Jantke, A. Gal, and K. Kutsche (2003). Interaction of alphaPIX (ARHGEF6) with beta-parvin (PARVB) suggests an involvement of alphaPIX in integrin-mediated signaling. Hum. Mol. Genet. 12: 155–167.

    Google Scholar 

  106. K. A. Clark, M. McGrail, and M. C. Beckerle (2003). Analysis of PINCH function in Drosophila demonstrates its requirement in integrin-dependent cellular processes. Development 130: 2611–2621.

    Google Scholar 

  107. C. G. Zervas, S. L. Gregory, and N. H. Brown (2001). Drosophila integrin-linked kinase is required at sites of integrin adhesion to link the cytoskeleton to the plasma membrane. J. Cell Biol. 152: 1007–1018.

    Google Scholar 

  108. A. C. Mackinnon, H. Qadota, K. R. Norman, D. G. Moerman, and B. D. Williams (2002). C. elegans PAT-4/ILK functions as an adaptor protein within integrin adhesion complexes. Curr. Biol. 12: 787–797.

    Google Scholar 

  109. X. Lin, H. Qadota, D. G. Moerman, and B. D. Williams (2003). C. elegans PAT-6/Actopaxin plays a critical role in the assembly of integrin adhesion complexes in vivo. Curr. Biol. 13: 922–932.

    Google Scholar 

  110. A. Novak, S. C. Hsu, C. Leung-Hagesteijn, G. Radeva, J. Papkoff, R. Montesano, C. Roskelley, R. Grosschedl, and S. Dedhar (1998). Cell adhesion and the integrin-linked kinase regulate the LEF-1 and beta-catenin signaling pathways. Proc. Natl. Acad. Sci. U.S.A. 95: 4374–4379.

    Google Scholar 

  111. A. A. Troussard, P. Costello, T. N. Yoganathan, S. Kumagai, C. D. Roskelley, and S. Dedhar (2000). The integrin linked kinase (ILK) induces an invasive phenotype via AP-1 transcription factor-dependent upregulation of matrix metalloproteinase 9 (MMP-9). Oncogene 19: 5444–5452.

    Google Scholar 

  112. A. Marotta, C. Tan, V. Gray, S. Malik, S. Gallinger, J. Sanghera, B. Dupuis, D. Owen, S. Dedhar, and B. Salh (2001). Dysregulation of integrin-linked kinase (ILK) signaling in colonic polyposis. Oncogene 20: 6250–6257.

    Google Scholar 

  113. A. Marotta, K. Parhar, D. Owen, S. Dedhar, and B. Salh (2003). Characterisation of integrin-linked kinase signaling in sporadic human colon cancer. Br. J. Cancer 88: 1755–1762.

    Google Scholar 

  114. D. E. White, R. D. Cardiff, S. Dedhar, and W. J. Muller (2001). Mammary epithelial-specific expression of theintegrin-linked kinase (ILK) results in the induction of mammary gland hyperplasias and tumors in transgenic mice. Oncogene 20: 7064–7072.

    Google Scholar 

  115. M. D'Amico, J. Hulit, D. F. Amanatullah, B. T. Zafonte, C. Albanese, B. Bouzahzah, M. Fu, L. H. Augenlicht, L. A. Donehower, K. Takemaru, R. T. Moon, R. Davis, M. P. Lisanti, M. Shtutman, J. Zhurinsky, A. Ben-Ze'ev, A. A. Troussard, S. Dedhar, and R. G. Pestell (2000). The integrin-linked kinase regulates the cyclin D1 gene through glycogen synthase kinase 3beta and cAMP-responsive element-binding protein-dependent pathways. J. Biol. Chem. 275: 32649–32657.

    Google Scholar 

  116. S. Attwell, C. Roskelley, and S. Dedhar (2000). The integrin-linked kinase (ILK) suppresses anoikis. Oncogene 19: 3811–3815.

    Google Scholar 

  117. A. Somasiri, A. Howarth, D. Goswami, S. Dedhar, and C. D. Roskelley (2001). Overexpression of the integrin-linked kinase mesenchymally transforms mammary epithelial cells. J. Cell Sci. 114: 1125–1136.

    Google Scholar 

  118. A. Vespa, A. J. Darmon, C. E. Turner, S. J. D'Souza, and L. Dagnino (2003). Ca2+-dependent localization of integrin-linked kinase to cell junctions in differentiating keratinocytes. J. Biol. Chem. 278: 11528–11535.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Charles H. Streuli.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schatzmann, F., Marlow, R. & Streuli, C.H. Integrin Signaling and Mammary Cell Function. J Mammary Gland Biol Neoplasia 8, 395–408 (2003). https://doi.org/10.1023/B:JOMG.0000017427.14751.8c

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:JOMG.0000017427.14751.8c

Navigation