This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Bill, H. M.
Right arrow Articles by Miranti, C. K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bill, H. M.
Right arrow Articles by Miranti, C. K.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, October 2004, p. 8586-8599, Vol. 24, No. 19
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.19.8586-8599.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Epidermal Growth Factor Receptor-Dependent Regulation of Integrin-Mediated Signaling and Cell Cycle Entry in Epithelial Cells

Heather M. Bill,1,{dagger} Beatrice Knudsen,2 Sheri L. Moores,3 Senthil K. Muthuswamy,3,{ddagger} Vikram R. Rao,3,§ Joan S. Brugge,3 and Cindy K. Miranti1*

Van Andel Research Institute, Grand Rapids, Michigan,1 Division of Public Health Sciences, Program in Cancer Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington,2 Department of Cell Biology, Harvard Medical School, Boston, Massachusetts3

Received 20 October 2003/ Returned for modification 9 December 2003/ Accepted 16 June 2004

Integrin-mediated adhesion of epithelial cells to extracellular matrix (ECM) proteins induces prolonged tyrosine phosphorylation and partial activation of epidermal growth factor receptor (EGFR) in an integrin-dependent and EGFR ligand-independent manner. Integrin-mediated activation of EGFR in epithelial cells is required for multiple signal transduction events previously shown to be induced by cell adhesion to matrix proteins, including tyrosine phosphorylation of Shc, Cbl, and phospholipase C{gamma}, and activation of the Ras/Erk and phosphatidylinositol 3'-kinase/Akt signaling pathways. In contrast, activation of focal adhesion kinase, Src, and protein kinase C, adhesion to matrix proteins, cell spreading, migration, and actin cytoskeletal rearrangements are induced independently of EGFR kinase activity. The ability of integrins to induce the activation of EGFR and its subsequent regulation of Erk and Akt activation permitted adhesion-dependent induction of cyclin D1 and p21, Rb phosphorylation, and activation of cdk4 in epithelial cells in the absence of exogenous growth factors. Adhesion of epithelial cells to the ECM failed to efficiently induce degradation of p27, to induce cdk2 activity, or to induce Myc and cyclin A synthesis; subsequently, cells did not progress into S phase. Treatment of ECM-adherent cells with EGF, or overexpression of EGFR or Myc, resulted in restoration of late-G1 cell cycle events and progression into S phase. These results indicate that partial activation of EGFR by integrin receptors plays an important role in mediating events triggered by epithelial cell attachment to ECM; EGFR is necessary for activation of multiple integrin-induced signaling enzymes and sufficient for early events in G1 cell cycle progression. Furthermore, these findings suggest that EGFR or Myc overexpression may provoke ligand-independent proliferation in matrix-attached cells in vivo and could contribute to carcinoma development.

* Corresponding author. Mailing address: Van Andel Research Institute, 333 Bostwick Ave., SE, Grand Rapids, MI 49503. Phone: (616) 234-5358. Fax: (616) 234-5359. E-mail: cindy.miranti{at}vai.org.

{dagger} Present address: Department of Pathology, Vanderbilt University, Nashville, TN 37232.

{ddagger} Present address: Cold Spring Harbor Labs, Cold Spring Harbor, NY 11724.

§ Present address: Wyeth Research, Cambridge, MA 02140.

Molecular and Cellular Biology, October 2004, p. 8586-8599, Vol. 24, No. 19
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.19.8586-8599.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Streuli, C. H. (2009). Integrins and cell-fate determination. J. Cell Sci. 122: 171-177 [Abstract] [Full Text]  
  • Shema, E., Tirosh, I., Aylon, Y., Huang, J., Ye, C., Moskovits, N., Raver-Shapira, N., Minsky, N., Pirngruber, J., Tarcic, G., Hublarova, P., Moyal, L., Gana-Weisz, M., Shiloh, Y., Yarden, Y., Johnsen, S. A., Vojtesek, B., Berger, S. L., Oren, M. (2008). The histone H2B-specific ubiquitin ligase RNF20/hBRE1 acts as a putative tumor suppressor through selective regulation of gene expression. Genes Dev. 22: 2664-2676 [Abstract] [Full Text]  
  • Xiang, B., Chatti, K., Qiu, H., Lakshmi, B., Krasnitz, A., Hicks, J., Yu, M., Miller, W. T., Muthuswamy, S. K. (2008). Brk is coamplified with ErbB2 to promote proliferation in breast cancer. Proc. Natl. Acad. Sci. USA 105: 12463-12468 [Abstract] [Full Text]  
  • Shao, L.-j., Shi, H. Y., Ayala, G., Rowley, D., Zhang, M. (2008). Haploinsufficiency of the Maspin Tumor Suppressor Gene Leads to Hyperplastic Lesions in Prostate. Cancer Res. 68: 5143-5151 [Abstract] [Full Text]  
  • Unfried, K., Sydlik, U., Bierhals, K., Weissenberg, A., Abel, J. (2008). Carbon nanoparticle-induced lung epithelial cell proliferation is mediated by receptor-dependent Akt activation. Am. J. Physiol. Lung Cell. Mol. Physiol. 294: L358-L367 [Abstract] [Full Text]  
  • Mimeault, M., Batra, S. K. (2007). Interplay of distinct growth factors during epithelial mesenchymal transition of cancer progenitor cells and molecular targeting as novel cancer therapies. Ann Oncol 18: 1605-1619 [Abstract] [Full Text]  
  • Edick, M. J., Tesfay, L., Lamb, L. E., Knudsen, B. S., Miranti, C. K. (2007). Inhibition of Integrin-mediated Crosstalk with Epidermal Growth Factor Receptor/Erk or Src Signaling Pathways in Autophagic Prostate Epithelial Cells Induces Caspase-independent Death. Mol. Biol. Cell 18: 2481-2490 [Abstract] [Full Text]  
  • Mukoyama, Y., Utani, A., Matsui, S., Zhou, S., Miyachi, Y., Matsuyoshi, N. (2007). T-cadherin enhances cell-matrix adhesiveness by regulating {beta}1 integrin trafficking in cutaneous squamous carcinoma cells. GENES CELLS 12: 787-796 [Abstract] [Full Text]  
  • Gentilini, D., Busacca, M., Di Francesco, S., Vignali, M., Vigano, P., Di Blasio, A.M. (2007). PI3K/Akt And ERK1/2 signalling pathways are involved in endometrial cell migration induced by 17{beta}-estradiol and growth factors. Mol Hum Reprod 13: 317-322 [Abstract] [Full Text]  
  • Fridman, J. S., Caulder, E., Hansbury, M., Liu, X., Yang, G., Wang, Q., Lo, Y., Zhou, B.-B., Pan, M., Thomas, S. M., Grandis, J. R., Zhuo, J., Yao, W., Newton, R. C., Friedman, S. M., Scherle, P. A., Vaddi, K. (2007). Selective Inhibition of ADAM Metalloproteases as a Novel Approach for Modulating ErbB Pathways in Cancer. Clin. Cancer Res. 13: 1892-1902 [Abstract] [Full Text]  
  • Koon, H.-W., Zhao, D., Zhan, Y., Moyer, M. P., Pothoulakis, C. (2007). Substance P mediates antiapoptotic responses in human colonocytes by Akt activation. Proc. Natl. Acad. Sci. USA 104: 2013-2018 [Abstract] [Full Text]  
  • Yan, W., Shao, R. (2006). Transduction of a Mesenchyme-specific Gene Periostin into 293T Cells Induces Cell Invasive Activity through Epithelial-Mesenchymal Transformation. J. Biol. Chem. 281: 19700-19708 [Abstract] [Full Text]  
  • Sawhney, R. S., Cookson, M. M., Omar, Y., Hauser, J., Brattain, M. G. (2006). Integrin {alpha}2-mediated ERK and Calpain Activation Play a Critical Role in Cell Adhesion and Motility via Focal Adhesion Kinase Signaling: IDENTIFICATION OF A NOVEL SIGNALING PATHWAY. J. Biol. Chem. 281: 8497-8510 [Abstract] [Full Text]  
  • Campos, L. S., Decker, L., Taylor, V., Skarnes, W. (2006). Notch, Epidermal Growth Factor Receptor, and beta1-Integrin Pathways Are Coordinated in Neural Stem Cells. J. Biol. Chem. 281: 5300-5309 [Abstract] [Full Text]  
  • Naylor, M. J., Li, N., Cheung, J., Lowe, E. T., Lambert, E., Marlow, R., Wang, P., Schatzmann, F., Wintermantel, T., Schuetz, G., Clarke, A. R., Mueller, U., Hynes, N. E., Streuli, C. H. (2005). Ablation of {beta}1 integrin in mammary epithelium reveals a key role for integrin in glandular morphogenesis and differentiation. JCB 171: 717-728 [Abstract] [Full Text]  
  • del Carmen, M. G., Rizvi, I., Chang, Y., Moor, A. C. E., Oliva, E., Sherwood, M., Pogue, B., Hasan, T. (2005). Synergism of Epidermal Growth Factor Receptor-Targeted Immunotherapy With Photodynamic Treatment of Ovarian Cancer In Vivo. JNCI J Natl Cancer Inst 97: 1516-1524 [Abstract] [Full Text]  
  • Dicker, A. P., Rodeck, U. (2005). Predicting the Future From Trials of the Past: Epidermal Growth Factor Receptor Expression and Outcome of Fractionated Radiation Therapy Trials. JCO 23: 5437-5439 [Full Text]  
  • Zhang, X., Wang, J. F., Chandran, B., Persaud, K., Pytowski, B., Fingeroth, J., Groopman, J. E. (2005). Kaposi's Sarcoma-associated Herpesvirus Activation of Vascular Endothelial Growth Factor Receptor 3 Alters Endothelial Function and Enhances Infection. J. Biol. Chem. 280: 26216-26224 [Abstract] [Full Text]  
  • Dong, J., Opresko, L. K., Chrisler, W., Orr, G., Quesenberry, R. D., Lauffenburger, D. A., Wiley, H. S. (2005). The Membrane-anchoring Domain of Epidermal Growth Factor Receptor Ligands Dictates Their Ability to Operate in Juxtacrine Mode. Mol. Biol. Cell 16: 2984-2998 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»