The intracellular functions of alpha6beta4 integrin are regulated by EGF

doi:10.1083/jcb.134.1.241

This Article

	Full Text (PDF, 3206K)
	Alert me when this article is cited
	Citation Map

Services

	Email this article
	Similar articles in this journal
	Similar articles in PubMed
	Alert me to new content in the JCB
	Download to citation manager

Citing Articles

	Citing Articles via HighWire
	Citing Articles via CrossRef
	Citing Articles via Google Scholar

Google Scholar

	Articles by Mainiero, F.
	Articles by Giancotti, F. G.
	Search for Related Content

PubMed

	PubMed Citation
	Articles by Mainiero, F.
	Articles by Giancotti, F. G.


Social Bookmarking

	What's this?

ARTICLES

The intracellular functions of alpha6beta4 integrin are regulated by EGF

F Mainiero, A Pepe, M Yeon, Y Ren and FG Giancotti
Department of Pathology, Kaplan Cancer Center, New York University School of Medicine, New York 10016, USA.

Upon ligand binding, the alpha6beta4 integrin becomes phosphorylated on tyrosine residues and combines sequentially with the adaptor molecules Shc and Grb2, linking to the ras pathway, and with cytoskeletal elements of hemidesmosomes. Since alpha6beta4 is expressed in a variety of tissues regulated by the EGF receptor (EGFR), we have examined the effect of EGF on the cytoskeletal and signaling functions of alpha6beta4. Experiments of immunoblotting with anti-phosphotyrosine antibodies and immunoprecipitation followed by phosphoamino acid analysis and phosphopeptide mapping showed that activation of the EGFR causes phosphorylation of the beta4 subunit at multiple tyrosine residues, and this event requires ligation of the integrin by laminins or specific antibodies. Immunoprecipitation experiments indicated that stimulation with EGF does not result in association of alpha6beta4 with Shc. In contrast, EGF can partially suppress the recruitment of Shc to ligated alpha6beta4. Immunofluorescent analysis revealed that EGF treatment does not induce increased assembly of hemidesmosomes, but instead causes a deterioration of these adhesive structures. Finally, Boyden chamber assays indicated that exposure to EGF results in upregulation of alpha6beta4-mediated cell migration toward laminins. We conclude that EGF-dependent signals suppress the association of activated alpha6beta4 with both signaling and cytoskeletal molecules, but upregulate alpha6beta4-dependent cell migration. The changes in alpha6beta4 function induced by EGF may play a role during wound healing and tumorigenesis.
Add to CiteULike CiteULike Add to Complore Complore Add to Connotea Connotea Add to Del.icio.us Del.icio.us Add to Digg Digg Facebook Add to Reddit Reddit Add to Technorati Technorati Twitter What's this?

This article has been cited by other articles:

Kim, T. H., Kim, H. I., Soung, Y. H., Shaw, L. A., Chung, J. (2009). Integrin ({alpha}6{beta}4) Signals Through Src to Increase Expression of S100A4, a Metastasis-Promoting Factor: Implications for Cancer Cell Invasion. Mol Cancer Res 7: 1605-1612 [Abstract] [Full Text]
Chen, M., Sinha, M., Luxon, B. A., Bresnick, A. R., O'Connor, K. L. (2009). Integrin {alpha}6{beta}4 Controls the Expression of Genes Associated with Cell Motility, Invasion, and Metastasis, Including S100A4/Metastasin. J. Biol. Chem. 284: 1484-1494 [Abstract] [Full Text]
Germain, E. C., Santos, T. M., Rabinovitz, I. (2009). Phosphorylation of a Novel Site on the {beta}4 Integrin at the Trailing Edge of Migrating Cells Promotes Hemidesmosome Disassembly. Mol. Biol. Cell 20: 56-67 [Abstract] [Full Text]
Lu, S., Simin, K., Khan, A., Mercurio, A. M. (2008). Analysis of Integrin {beta}4 Expression in Human Breast Cancer: Association with Basal-like Tumors and Prognostic Significance. Clin. Cancer Res. 14: 1050-1058 [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]
Stepp, M. A., Liu, Y., Pal-Ghosh, S., Jurjus, R. A., Tadvalkar, G., Sekaran, A., LoSicco, K., Jiang, L., Larsen, M., Li, L., Yuspa, S. H. (2007). Reduced migration, altered matrix and enhanced TGFbeta1 signaling are signatures of mouse keratinocytes lacking Sdc1. J. Cell Sci. 120: 2851-2863 [Abstract] [Full Text]
Ogawa, T., Tsubota, Y., Hashimoto, J., Kariya, Y., Miyazaki, K. (2007). The Short Arm of Laminin {gamma}2 Chain of Laminin-5 (Laminin-332) Binds Syndecan-1 and Regulates Cellular Adhesion and Migration by Suppressing Phosphorylation of Integrin beta4 Chain. Mol. Biol. Cell 18: 1621-1633 [Abstract] [Full Text]
Folgiero, V., Bachelder, R. E., Bon, G., Sacchi, A., Falcioni, R., Mercurio, A. M. (2007). The {alpha}6{beta}4 Integrin Can Regulate ErbB-3 Expression: Implications for {alpha}6{beta}4 Signaling and Function. Cancer Res. 67: 1645-1652 [Abstract] [Full Text]
Bertotti, A., Comoglio, P. M., Trusolino, L. (2006). {beta}4 integrin activates a Shp2-Src signaling pathway that sustains HGF-induced anchorage-independent growth. JCB 175: 993-1003 [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]
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]
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]
Fukumoto, S., Miner, J. H., Ida, H., Fukumoto, E., Yuasa, K., Miyazaki, H., Hoffman, M. P., Yamada, Y. (2006). Laminin {alpha}5 Is Required for Dental Epithelium Growth and Polarity and the Development of Tooth Bud and Shape. J. Biol. Chem. 281: 5008-5016 [Abstract] [Full Text]
Yoon, S.-O., Shin, S., Mercurio, A. M. (2005). Hypoxia Stimulates Carcinoma Invasion by Stabilizing Microtubules and Promoting the Rab11 Trafficking of the {alpha}6{beta}4 Integrin. Cancer Res. 65: 2761-2769 [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. JCB 167: 1231-1240 [Abstract] [Full Text]
Bill, H. M., Knudsen, B., Moores, S. L., Muthuswamy, S. K., Rao, V. R., Brugge, J. S., Miranti, C. K. (2004). Epidermal Growth Factor Receptor-Dependent Regulation of Integrin-Mediated Signaling and Cell Cycle Entry in Epithelial Cells. Mol. Cell. Biol. 24: 8586-8599 [Abstract] [Full Text]
Rabinovitz, I., Tsomo, L., Mercurio, A. M. (2004). Protein Kinase C-{alpha} Phosphorylation of Specific Serines in the Connecting Segment of the {beta}4 Integrin Regulates the Dynamics of Type II Hemidesmosomes. Mol. Cell. Biol. 24: 4351-4360 [Abstract] [Full Text]
Joly, D., Morel, V., Hummel, A., Ruello, A., Nusbaum, P., Patey, N., Noel, L.-H., Rousselle, P., Knebelmann, B. (2003). {beta}4 Integrin and Laminin 5 Are Aberrantly Expressed in Polycystic Kidney Disease: Role in Increased Cell Adhesion and Migration. Am. J. Pathol. 163: 1791-1800 [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]
Tsuruta, D., Hopkinson, S. B., Lane, K. D., Werner, M. E., Cryns, V. L., Jones, J. C. R. (2003). Crucial Role of the Specificity-determining Loop of the Integrin {beta}4 Subunit in the Binding of Cells to Laminin-5 and Outside-in Signal Transduction. J. Biol. Chem. 278: 38707-38714 [Abstract] [Full Text]
Owens, D. M., Romero, M. R., Gardner, C., Watt, F. M. (2003). Suprabasal {alpha}6{beta}4 integrin expression in epidermis results in enhanced tumourigenesis and disruption of TGF{beta} signalling. J. Cell Sci. 116: 3783-3791 [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]
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]
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. JCB 155: 447-458 [Abstract] [Full Text]
Alt, A., Ohba, M., Li, L., Gartsbein, M., Belanger, A., Denning, Mitchell. F., Kuroki, T., Yuspa, S. H., Tennenbaum, T. (2001). Protein Kinase C{{delta}}-mediated Phosphorylation of {{alpha}}6{beta}4 Is Associated with Reduced Integrin Localization to the Hemidesmosome and Decreased Keratinocyte Attachment. Cancer Res. 61: 4591-4598 [Abstract] [Full Text]
Payne, E., Bowles, M. R., Don, A., Hancock, J. F., McMillan, N. A. J. (2001). Human Papillomavirus Type 6b Virus-Like Particles Are Able To Activate the Ras-MAP Kinase Pathway and Induce Cell Proliferation. J. Virol. 75: 4150-4157 [Abstract] [Full Text]
Edlund, M., Miyamoto, T., Sikes, R. A., Ogle, R., Laurie, G. W., Farach-Carson, M. C., Otey, C. A., Zhau, H. E., Chung, L. W. K. (2001). Integrin Expression and Usage by Prostate Cancer Cell Lines on Laminin Substrata. Cell Growth Differ. 12: 99-107 [Abstract] [Full Text]
Steffensen, B., Hakkinen, L., Larjava, H. (2001). Proteolytic Events of Wound-Healing -- Coordinated Interactions Among Matrix Metalloproteinases (MMPs), Integrins, and Extracellular Matrix Molecules. CROBM 12: 373-398 [Abstract] [Full Text]
Raghavan, S., Bauer, C., Mundschau, G., Li, Q., Fuchs, E. (2000). Conditional Ablation of {beta}1 Integrin in Skin: Severe Defects in Epidermal Proliferation, Basement Membrane Formation, and Hair Follicle Invagination. JCB 150: 1149-1160 [Abstract] [Full Text]
Michelson, P. H., Tigue, M., Jones, J. C.R. (2000). Human Bronchial Epithelial Cells Secrete Laminin 5, Express Hemidesmosomal Proteins, and Assemble Hemidesmosomes. J. Histochem. Cytochem. 48: 535-544 [Abstract] [Full Text]
Gambaletta, D., Marchetti, A., Benedetti, L., Mercurio, A. M., Sacchi, A., Falcioni, R. (2000). Cooperative Signaling between alpha 6beta 4 Integrin and ErbB-2 Receptor Is Required to Promote Phosphatidylinositol 3-Kinase-dependent Invasion. J. Biol. Chem. 275: 10604-10610 [Abstract] [Full Text]
Yu, X, Miyamoto, S, Mekada, E (2000). Integrin alpha 2 beta 1-dependent EGF receptor activation at cell-cell contact sites. J. Cell Sci. 113: 2139-2147 [Abstract]
Akamatsu, M., Aota, S.-i., Suwa, A., Ueda, K., Amachi, T., Yamada, K. M., Akiyama, S. K., Kioka, N. (1999). Vinexin Forms a Signaling Complex with Sos and Modulates Epidermal Growth Factor-induced c-Jun N-terminal Kinase/Stress-activated Protein Kinase Activities. J. Biol. Chem. 274: 35933-35937 [Abstract] [Full Text]
Rabinovitz, I., Toker, A., Mercurio, A. M. (1999). Protein Kinase C-Dependent Mobilization of the {alpha}6{beta}4 Integrin from Hemidesmosomes and Its Association with Actin-Rich Cell Protrusions Drive the Chemotactic Migration of Carcinoma Cells. JCB 146: 1147-1160 [Abstract] [Full Text]
Adelsman, M. A., McCarthy, J. B., Shimizu, Y. (1999). Stimulation of beta 1-Integrin Function by Epidermal Growth Factor and Heregulin-beta Has Distinct Requirements for erbB2 but a Similar Dependence on Phosphoinositide 3-OH Kinase. Mol. Biol. Cell 10: 2861-2878 [Abstract] [Full Text]
Chen, K.-D., Li, Y.-S., Kim, M., Li, S., Yuan, S., Chien, S., Shyy, J. Y-J. (1999). Mechanotransduction in Response to Shear Stress. ROLES OF RECEPTOR TYROSINE KINASES, INTEGRINS, AND Shc. J. Biol. Chem. 274: 18393-18400 [Abstract] [Full Text]
Crowe, D.L., Milo, G.E., Shuler, C.E. (1999). Keratin 19 Downregulation by Oral Squamous Cell Carcinoma Lines Increases Invasive Potential. JDR 78: 1256-1263 [Abstract]
Luetteke, N., Qiu, T., Fenton, S., Troyer, K., Riedel, R., Chang, A, Lee, D. (1999). Targeted inactivation of the EGF and amphiregulin genes reveals distinct roles for EGF receptor ligands in mouse mammary gland development. Development 126: 2739-2750 [Abstract]
Rabinovitz, I., Mercurio, A. M. (1997). The Integrin {alpha}6{beta}4 Functions in Carcinoma Cell Migration on Laminin-1 by Mediating the Formation and Stabilization of Actin-containing Motility Structures. JCB 139: 1873-1884 [Abstract] [Full Text]
Price, A. A., Cumberbatch, M., Kimber, I., Ager, A. (1997). {alpha}6 Integrins Are Required for Langerhans Cell Migration from the Epidermis. JEM 186: 1725-1735 [Abstract] [Full Text]
Ferrigno, O., Virolle, T., Galliano, M.-F., Chauvin, N., Ortonne, J.-P., Meneguzzi, G., Aberdam, D. (1997). Murine Laminin alpha 3A and alpha 3B Isoform Chains Are Generated by Usage of Two Promoters and Alternative Splicing. J. Biol. Chem. 272: 20502-20507 [Abstract] [Full Text]
Xu, Y., Guo, D.-F., Davidson, M., Inagami, T., Carpenter, G. (1997). Interaction of the Adaptor Protein Shc and the Adhesion Molecule Cadherin. J. Biol. Chem. 272: 13463-13466 [Abstract] [Full Text]
Borradori, L., Koch, P. J., Niessen, C. M., Erkeland, S., Leusden, M. R. v., Sonnenberg, A. (1997). The Localization of Bullous Pemphigoid Antigen 180 (BP180) in Hemidesmosomes Is Mediated by Its Cytoplasmic Domain and Seems to be Regulated by the {beta}4 Integrin Subunit. JCB 136: 1333-1347 [Abstract] [Full Text]
Stahl, S, Weitzman, S, Jones, J. (1997). The role of laminin-5 and its receptors in mammary epithelial cell branching morphogenesis. J. Cell Sci. 110: 55-63 [Abstract]
Dans, M., Gagnoux-Palacios, L., Blaikie, P., Klein, S., Mariotti, A., Giancotti, F. G. (2001). Tyrosine Phosphorylation of the beta 4 Integrin Cytoplasmic Domain Mediates Shc Signaling to Extracellular Signal-regulated Kinase and Antagonizes Formation of Hemidesmosomes. J. Biol. Chem. 276: 1494-1502 [Abstract] [Full Text]
Favre, B., Fontao, L., Koster, J., Shafaatian, R., Jaunin, F., Saurat, J.-H., Sonnenberg, A., Borradori, L. (2001). The Hemidesmosomal Protein Bullous Pemphigoid Antigen 1 and the Integrin beta 4 Subunit Bind to ERBIN. MOLECULAR CLONING OF MULTIPLE ALTERNATIVE SPLICE VARIANTS OF ERBIN AND ANALYSIS OF THEIR TISSUE EXPRESSION. J. Biol. Chem. 276: 32427-32436 [Abstract] [Full Text]
Abdel-Ghany, M., Cheng, H.-C., Elble, R. C., Pauli, B. U. (2001). The Breast Cancer beta 4 Integrin and Endothelial Human CLCA2 Mediate Lung Metastasis. J. Biol. Chem. 276: 25438-25446 [Abstract] [Full Text]