This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow An erratum has been published
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 Nikolopoulos, S. N.
Right arrow Articles by Giancotti, F. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nikolopoulos, S. N.
Right arrow Articles by Giancotti, F. G.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, July 2005, p. 6090-6102, Vol. 25, No. 14
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.14.6090-6102.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Targeted Deletion of the Integrin ß4 Signaling Domain Suppresses Laminin-5-Dependent Nuclear Entry of Mitogen-Activated Protein Kinases and NF-{kappa}B, Causing Defects in Epidermal Growth and Migration

Sotiris N. Nikolopoulos,1,{dagger} Pamela Blaikie,1,{dagger} Toshiaki Yoshioka,1 Wenjun Guo,1 Claudia Puri,2 Carlo Tacchetti,2 and Filippo G. Giancotti1*

Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York,1 IFOM Center of Cell Oncology and Ultrastructure, Department of Experimental Medicine, University of Genova, Genoa, Italy2

Received 10 November 2004/ Returned for modification 20 December 2004/ Accepted 28 April 2005

The {alpha}6ß4 integrin—a laminin-5 receptor—mediates assembly of hemidesmosomes and recruitment of Shc and phosphoinositide 3-kinase through the unique cytoplasmic extension of ß4. Mice carrying a targeted deletion of the signaling domain of ß4 develop normally and do not display signs of skin fragility. The epidermis of these mice contains well-structured hemidesmosomes and adheres stably to the basement membrane. However, it is hypoplastic due to reduced proliferation of basal keratinocytes and undergoes wound repair at a reduced rate. Keratinocytes from ß4 mutant mice undergo extensive spreading but fail to proliferate and migrate in response to epidermal growth factor (EGF) on laminin-5. EGF causes significant phosphorylation of extracellular signal-regulated kinase (ERK) and Jun N-terminal protein kinase (JNK) and phosphorylation and degradation of I{kappa}B in ß4 mutant cells adhering to laminin-5. Unexpectedly, however, ERK, JNK, and NF-{kappa}B remain in the cytoplasm in ß4 mutant cells on laminin-5, whereas they enter effectively into the nucleus in the same cells on fibronectin or in wild-type cells on both matrix proteins. Inhibitor studies indicate that {alpha}6ß4 promotes keratinocyte proliferation and migration through its effect on NF-{kappa}B and P-JNK. These findings provide evidence that ß4 signaling promotes epidermal growth and wound healing through a previously unrecognized effect on nuclear translocation of NF-{kappa}B and mitogen-activated protein kinases.

* Corresponding author. Mailing address: Memorial Sloan-Kettering Cancer Center, Box 216, 1275 York Avenue, New York, NY 10021. Phone: (212) 639-6998. Fax: (212) 794-6236. E-mail: f-giancotti{at}ski.mskcc.org.

{dagger} S.N.N. and P.B. contributed equally.

Molecular and Cellular Biology, July 2005, p. 6090-6102, Vol. 25, No. 14
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.14.6090-6102.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Hamill, K. J., Hopkinson, S. B., DeBiase, P., Jones, J. C.R. (2009). BPAG1e Maintains Keratinocyte Polarity through {beta}4 Integrin-mediated Modulation of Rac 1 and Cofilin Activities. Mol. Biol. Cell 20: 2954-2962 [Abstract] [Full Text]  
  • Velozo, J, Aguilera, S, Alliende, C, Ewert, P, Molina, C, Perez, P, Leyton, L, Quest, A, Brito, M, Gonzalez, S, Leyton, C, Hermoso, M, Romo, R, Gonzalez, M-J (2009). Severe alterations in expression and localisation of {alpha}6{beta}4 integrin in salivary gland acini from patients with Sjogren syndrome. Ann Rheum Dis 68: 991-996 [Abstract] [Full Text]  
  • Gonzalez, A. M., Claiborne, J., Jones, J. C. R. (2008). Integrin Cross-talk in Endothelial Cells Is Regulated by Protein Kinase A and Protein Phosphatase 1. J. Biol. Chem. 283: 31849-31860 [Abstract] [Full Text]  
  • Fitsialos, G., Bourget, I., Augier, S., Ginouves, A., Rezzonico, R., Odorisio, T., Cianfarani, F., Virolle, T., Pouyssegur, J., Meneguzzi, G., Berra, E., Ponzio, G., Busca, R. (2008). HIF1 transcription factor regulates laminin-332 expression and keratinocyte migration. J. Cell Sci. 121: 2992-3001 [Abstract] [Full Text]  
  • Reitzel, A. M., Sullivan, J. C., Traylor-knowles, N., Finnerty, J. R. (2008). Genomic Survey of Candidate Stress-Response Genes in the Estuarine Anemone Nematostella vectensis. Biol. Bull. 214: 233-254 [Abstract] [Full Text]  
  • Tran, M., Rousselle, P., Nokelainen, P., Tallapragada, S., Nguyen, N. T., Fincher, E. F., Marinkovich, M. P. (2008). Targeting a Tumor-Specific Laminin Domain Critical for Human Carcinogenesis. Cancer Res. 68: 2885-2894 [Abstract] [Full Text]  
  • Kligys, K., Claiborne, J. N., DeBiase, P. J., Hopkinson, S. B., Wu, Y., Mizuno, K., Jones, J. C. R. (2007). The Slingshot Family of Phosphatases Mediates Rac1 Regulation of Cofilin Phosphorylation, Laminin-332 Organization, and Motility Behavior of Keratinocytes. J. Biol. Chem. 282: 32520-32528 [Abstract] [Full Text]  
  • Raymond, K., Kreft, M., Song, J.-Y., Janssen, H., Sonnenberg, A. (2007). Dual Role of {alpha}6beta4 Integrin in Epidermal Tumor Growth: Tumor-suppressive Versus Tumor-promoting Function. Mol. Biol. Cell 18: 4210-4221 [Abstract] [Full Text]  
  • James, B. P., Bunch, T. A., Krishnamoorthy, S., Perkins, L. A., Brower, D. L. (2007). Nuclear Localization of the ERK MAP Kinase Mediated by Drosophila {alpha}PS2betaPS Integrin and Importin-7. Mol. Biol. Cell 18: 4190-4199 [Abstract] [Full Text]  
  • Wilhelmsen, K., Litjens, S. H.M., Kuikman, I., Margadant, C., van Rheenen, J., Sonnenberg, A. (2007). Serine Phosphorylation of the Integrin beta4 Subunit Is Necessary for Epidermal Growth Factor Receptor induced Hemidesmosome Disruption. Mol. Biol. Cell 18: 3512-3522 [Abstract] [Full Text]  
  • Werner, M. E., Chen, F., Moyano, J. V., Yehiely, F., Jones, J. C. R., Cryns, V. L. (2007). Caspase Proteolysis of the Integrin beta4 Subunit Disrupts Hemidesmosome Assembly, Promotes Apoptosis, and Inhibits Cell Migration. J. Biol. Chem. 282: 5560-5569 [Abstract] [Full Text]  
  • Sugawara, K., Tsuruta, D., Kobayashi, H., Ikeda, K., Hopkinson, S. B., Jones, J. C.R., Ishii, M. (2007). Spatial and Temporal Control of Laminin-332 (5) and -511 (10) Expression During Induction of Anagen Hair Growth. J. Histochem. Cytochem. 55: 43-55 [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]  
  • Mak, G. Z., Kavanaugh, G. M., Buschmann, M. M., Stickley, S. M., Koch, M., Goss, K. H., Waechter, H., Zuk, A., Matlin, K. S. (2006). Regulated Synthesis and Functions of Laminin 5 in Polarized Madin-Darby Canine Kidney Epithelial Cells. Mol. Biol. Cell 17: 3664-3677 [Abstract] [Full Text]  
  • Wilhelmsen, K., Litjens, S. H.M., Sonnenberg, A. (2006). Multiple Functions of the Integrin {alpha}6{beta}4 in Epidermal Homeostasis and Tumorigenesis. Mol. Cell. Biol. 26: 2877-2886 [Full Text]  
  • Ouyang, W., Li, J., Ma, Q., Huang, C. (2006). Essential roles of PI-3K/Akt/IKK{beta}/NF{kappa}B pathway in cyclin D1 induction by arsenite in JB6 Cl41 cells. Carcinogenesis 27: 864-873 [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»