Original Article

Inhibitory Role of 6ß4-associated erbB-2 and Phosphoinositide 3-Kinase in Keratinocyte Haptotactic Migration Dependent on 3ß1 Integrin

Correspondence to: Vito Quaranta, Department of Cell Biology, SBR12, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. Tel:(858) 784-8793 Fax:(858) 784-2246 E-mail:quaranta{at}scripps.edu.

Keratinocytes and other epithelial cells express two receptors for the basement membrane (BM) extracellular matrix component laminin-5 (Ln-5), integrins 3ß1 and 6ß4. While 3ß1 mediates adhesion, spreading, and migration (Kreidberg, J.A. 2000. Curr. Opin. Cell Biol. 12:548–553), 6ß4 is involved in BM anchorage via hemidesmosomes (Borradori, L., and A. Sonnenberg. 1999. J. Invest. Dermatol. 112:411–418). We investigated a possible regulatory interplay between 3ß1 and 6ß4 in cell motility using HaCaT keratinocytes as a model. We found that 6ß4 antibodies inhibit 3ß1-mediated migration on Ln-5, but only when migration is haptotactic (i.e., spontaneous or stimulated by 3ß1 activation), and not when chemotactic (i.e., triggered by epidermal growth factor receptor). Inhibition of migration by 6ß4 depends upon phosphoinositide 3-kinase (PI3-K) since it is abolished by PI3-K blockers and by dominant-negative PI3-K, and constitutively active PI3-K prevents haptotaxis. In HaCaT cells incubated with anti–6ß4 antibodies, activation of PI3-K is mediated by 6ß4-associated erbB-2, as indicated by erbB-2 autophosphorylation and erbB-2/p85 PI3-K coprecipitation. Furthermore, dominant-negative erbB-2 abolishes inhibition of haptotaxis by anti–6ß4 antibodies. These results support a model whereby (a) haptotactic cell migration on Ln-5 is regulated by concerted action of 3ß1 and 6ß4 integrins, (b) 6ß4-associated erbB-2 and PI3-K negatively affect haptotaxis, and (c) chemotaxis on Ln-5 is not affected by 6ß4 antibodies and may require PI3-K activity. This model could be of general relevance to motility of epithelial cells in contact with BM.

Key Words: erbB-2, integrin, keratinocytes, laminin-5, phosphoinositide 3-kinase

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Avvisato, C. L., Yang, X., Shah, S., Hoxter, B., Li, W., Gaynor, R., Pestell, R., Tozeren, A., Byers, S. W. (2007). Mechanical force modulates global gene expression and beta-catenin signaling in colon cancer cells. J. Cell Sci. 120: 2672-2682 [Abstract] [Full Text]  
• Sehgal, B. U., DeBiase, P. J., Matzno, S., Chew, T.-L., Claiborne, J. N., Hopkinson, S. B., Russell, A., Marinkovich, M. P., Jones, J. C. R. (2006). Integrin beta4 Regulates Migratory Behavior of Keratinocytes by Determining Laminin-332 Organization. J. Biol. Chem. 281: 35487-35498 [Abstract] [Full Text]  
• Pullar, C. E., Baier, B. S., Kariya, Y., Russell, A. J., Horst, B. A.J., Marinkovich, M. P., Isseroff, R. R. (2006). beta4 Integrin and Epidermal Growth Factor Coordinately Regulate Electric Field-mediated Directional Migration via Rac1. Mol. Biol. Cell 17: 4925-4935 [Abstract] [Full Text]  
• Culp, T. D., Budgeon, L. R., Marinkovich, M. P., Meneguzzi, G., Christensen, N. D. (2006). Keratinocyte-secreted laminin 5 can function as a transient receptor for human papillomaviruses by binding virions and transferring them to adjacent cells.. J. Virol. 80: 8940-8950 [Abstract] [Full Text]  
• Natarajan, E., Omobono, J. D. II, Guo, Z., Hopkinson, S., Lazar, A. J.F., Brenn, T., Jones, J. C., Rheinwald, J. G. (2006). A Keratinocyte Hypermotility/Growth-Arrest Response Involving Laminin 5 and p16INK4A Activated in Wound Healing and Senescence. Am. J. Pathol. 168: 1821-1837 [Abstract] [Full Text]  
• Winterwood, N. E., Varzavand, A., Meland, M. N., Ashman, L. K., Stipp, C. S. (2006). A Critical Role for Tetraspanin CD151 in {alpha}3beta1 and {alpha}6beta4 Integrin-dependent Tumor Cell Functions on Laminin-5. Mol. Biol. Cell 17: 2707-2721 [Abstract] [Full Text]  
• Chartier, N. T., Laine, M., Gout, S., Pawlak, G., Marie, C. A., Matos, P., Block, M. R., Jacquier-Sarlin, M. R. (2006). Laminin-5-integrin interaction signals through PI 3-kinase and Rac1b to promote assembly of adherens junctions in HT-29 cells. J. Cell Sci. 119: 31-46 [Abstract] [Full Text]  
• Aguirre, A., Rizvi, T. A., Ratner, N., Gallo, V. (2005). Overexpression of the Epidermal Growth Factor Receptor Confers Migratory Properties to Nonmigratory Postnatal Neural Progenitors. J. Neurosci. 25: 11092-11106 [Abstract] [Full Text]  
• Lund, C. V., Popkov, M., Magnenat, L., Barbas, C. F. III (2005). Zinc Finger Transcription Factors Designed for Bispecific Coregulation of ErbB2 and ErbB3 Receptors: Insights into ErbB Receptor Biology. Mol. Cell. Biol. 25: 9082-9091 [Abstract] [Full Text]  
• Gesierich, S., Paret, C., Hildebrand, D., Weitz, J., Zgraggen, K., Schmitz-Winnenthal, F. H., Horejsi, V., Yoshie, O., Herlyn, D., Ashman, L. K., Zoller, M. (2005). Colocalization of the Tetraspanins, CO-029 and CD151, with Integrins in Human Pancreatic Adenocarcinoma: Impact on Cell Motility. Clin. Cancer Res. 11: 2840-2852 [Abstract] [Full Text]  
• Hintermann, E., Yang, N., O'Sullivan, D., Higgins, J. M. G., Quaranta, V. (2005). Integrin {alpha}6{beta}4-erbB2 Complex Inhibits Haptotaxis by Up-regulating E-cadherin Cell-Cell Junctions in Keratinocytes. J. Biol. Chem. 280: 8004-8015 [Abstract] [Full Text]  
• Yang, X., Kovalenko, O. V., Tang, W., Claas, C., Stipp, C. S., Hemler, M. E. (2004). Palmitoylation supports assembly and function of integrin-tetraspanin complexes. J. Cell Biol. 167: 1231-1240 [Abstract] [Full Text]  
• Xu, K.-P., Riggs, A., Ding, Y., Yu, F.-S. X. (2004). Role of ErbB2 in Corneal Epithelial Wound Healing. IOVS 45: 4277-4283 [Abstract] [Full Text]  
• Dorfleutner, A., Hintermann, E., Tarui, T., Takada, Y., Ruf, W. (2004). Cross-talk of Integrin {alpha}3{beta}1 and Tissue Factor in Cell Migration. Mol. Biol. Cell 15: 4416-4425 [Abstract] [Full Text]  
• Bilban, M., Ghaffari-Tabrizi, N., Hintermann, E., Bauer, S., Molzer, S., Zoratti, C., Malli, R., Sharabi, A., Hiden, U., Graier, W., Knofler, M., Andreae, F., Wagner, O., Quaranta, V., Desoye, G. (2004). Kisspeptin-10, a KiSS-1/metastin-derived decapeptide, is a physiological invasion inhibitor of primary human trophoblasts. J. Cell Sci. 117: 1319-1328 [Abstract] [Full Text]  
• Wang, H., Fu, W., Im, J. H., Zhou, Z., Santoro, S. A., Iyer, V., DiPersio, C. M., Yu, Q.-C., Quaranta, V., Al-Mehdi, A., Muschel, R. J. (2004). Tumor cell {alpha}3{beta}1 integrin and vascular laminin-5 mediate pulmonary arrest and metastasis. J. Cell Biol. 164: 935-941 [Abstract] [Full Text]  
• Frank, D. E., Carter, W. G. (2004). Laminin 5 deposition regulates keratinocyte polarization and persistent migration. J. Cell Sci. 117: 1351-1363 [Abstract] [Full Text]  
• Poggi, A., Carosio, R., Fenoglio, D., Brenci, S., Murdaca, G., Setti, M., Indiveri, F., Scabini, S., Ferrero, E., Zocchi, M. R. (2004). Migration of V{delta}1 and V{delta}2 T cells in response to CXCR3 and CXCR4 ligands in healthy donors and HIV-1-infected patients: competition by HIV-1 Tat. Blood 103: 2205-2213 [Abstract] [Full Text]  
• Herlevsen, M., Schmidt, D.-S., Miyazaki, K., Zoller, M. (2003). The association of the tetraspanin D6.1A with the {alpha}6{beta}4 integrin supports cell motility and liver metastasis formation. J. Cell Sci. 116: 4373-4390 [Abstract] [Full Text]  
• Russell, A. J., Fincher, E. F., Millman, L., Smith, R., Vela, V., Waterman, E. A., Dey, C. N., Guide, S., Weaver, V. M., Marinkovich, M. P. (2003). {alpha}6{beta}4 integrin regulates keratinocyte chemotaxis through differential GTPase activation and antagonism of {alpha}3{beta}1 integrin. J. Cell Sci. 116: 3543-3556 [Abstract] [Full Text]  
• Ritch, P. A., Carroll, S. L., Sontheimer, H. (2003). Neuregulin-1 Enhances Motility and Migration of Human Astrocytic Glioma Cells. J. Biol. Chem. 278: 20971-20978 [Abstract] [Full Text]  
• Kendirgi, F., Barry, D. M., Griffis, E. R., Powers, M. A., Wente, S. R. (2003). An essential role for hGle1 nucleocytoplasmic shuttling in mRNA export. J. Cell Biol. 160: 1029-1040 [Abstract] [Full Text]  
• Hirosaki, T., Tsubota, Y., Kariya, Y., Moriyama, K., Mizushima, H., Miyazaki, K. (2002). Laminin-6 Is Activated by Proteolytic Processing and Regulates Cellular Adhesion and Migration Differently from Laminin-5. J. Biol. Chem. 277: 49287-49295 [Abstract] [Full Text]  
• Geuijen, C. A. W., Sonnenberg, A. (2002). Dynamics of the alpha 6beta 4 Integrin in Keratinocytes. Mol. Biol. Cell 13: 3845-3858 [Abstract] [Full Text]  
• Hintermann, E., Haake, S. K., Christen, U., Sharabi, A., Quaranta, V. (2002). Discrete Proteolysis of Focal Contact and Adherens Junction Components in Porphyromonas gingivalis-Infected Oral Keratinocytes: a Strategy for Cell Adhesion and Migration Disabling. Infect. Immun. 70: 5846-5856 [Abstract] [Full Text]  
• Chung, J., Bachelder, R. E., Lipscomb, E. A., Shaw, L. M., Mercurio, A. M. (2002). Integrin ({alpha}6{beta}4) regulation of eIF-4E activity and VEGF translation: a survival mechanism for carcinoma cells. J. Cell Biol. 158: 165-174 [Abstract] [Full Text]  
• Poggi, A., Zocchi, M. R., Carosio, R., Ferrero, E., Angelini, D. F., Galgani, S., Caramia, M. D., Bernardi, G., Borsellino, G., Battistini, L. (2002). Transendothelial Migratory Pathways of V{delta}1+TCR{gamma}{delta}+ and V{delta}2+TCR{gamma}{delta}+ T Lymphocytes from Healthy Donors and Multiple Sclerosis Patients: Involvement of Phosphatidylinositol 3 Kinase and Calcium Calmodulin-Dependent Kinase II. J. Immunol. 168: 6071-6077 [Abstract] [Full Text]  
• Mariotti, A., Kedeshian, P. A., Dans, M., Curatola, A. M., Gagnoux-Palacios, L., Giancotti, F. G. (2001). EGF-R signaling through Fyn kinase disrupts the function of integrin {alpha}6{beta}4 at hemidesmosomes: role in epithelial cell migration and carcinoma invasion. J. Cell Biol. 155: 447-458 [Abstract] [Full Text]  
• Shang, M., Koshikawa, N., Schenk, S., Quaranta, V. (2001). The LG3 Module of Laminin-5 Harbors a Binding Site for Integrin alpha 3beta 1 That Promotes Cell Adhesion, Spreading, and Migration. J. Biol. Chem. 276: 33045-33053 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents