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 Kiely, P. A.
Right arrow Articles by O'Connor, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kiely, P. A.
Right arrow Articles by O'Connor, R.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, June 2006, p. 4041-4051, Vol. 26, No. 11
0270-7306/06/$08.00+0     doi:10.1128/MCB.01868-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Insulin-Like Growth Factor I Controls a Mutually Exclusive Association of RACK1 with Protein Phosphatase 2A and ß1 Integrin To Promote Cell Migration

Patrick A. Kiely,1 Denise O'Gorman,1 Ken Luong,2 Dorit Ron,2 and Rosemary O'Connor1*

Cell Biology Laboratory, Department of Biochemistry, BioSciences Institute, National University of Ireland, Cork, Ireland,1 Gallo Research Center, Department of Neurology, University of California, San Francisco, Emeryville, California 946082

Received 23 September 2005/ Returned for modification 10 November 2005/ Accepted 17 March 2006

The WD repeat scaffolding protein RACK1 can mediate integration of the insulin-like growth factor I receptor (IGF-IR) and integrin signaling in transformed cells. To address the mechanism of RACK1 function, we searched for regulatory proteins that associate with RACK1 in an IGF-I-dependent manner. The serine threonine phosphatase protein phosphatase 2A (PP2A) was found associated with RACK1 in serum-starved cells, and it dissociated immediately upon stimulation with IGF-I. This dissociation of PP2A from RACK1 and an IGF-I-mediated decrease in cellular PP2A activity did not occur in cells expressing either the serine 1248 or tyrosine 1250/1251 mutants of the IGF-IR that do not interact with RACK1. Recombinant RACK1 could bind to PP2A in vitro and restore phosphatase activity to PP2A from IGF-I-stimulated cells. Ligation of integrins with fibronectin or Matrigel was sufficient to facilitate IGF-I-mediated dissociation of PP2A from RACK1 and also to recruit ß1 integrin as PP2A dissociated. By using TAT-fused N-terminal and C-terminal deletion mutants of RACK1, we determined that both PP2A and ß1 integrin interact in the C terminus of RACK1 within WD repeats 4 to 7. This suggests that integrin ligation displaces PP2A from RACK1. MCF-7 cells overexpressing RACK1 exhibited enhanced motility, which could be reversed by the PP2A inhibitor okadaic acid. Small interfering RNA-mediated suppression of RACK1 also decreased the migratory capacity of DU145 cells. Taken together, our findings indicate that RACK1 enhances IGF-I-mediated cell migration through its ability to exclusively associate with either ß1 integrin or PP2A in a complex at the IGF-IR.

* Corresponding author. Mailing address: Cell Biology Laboratory, Department of Biochemistry, BioSciences Institute, National University of Ireland, Cork, Ireland. Phone: 353 21 4901312. Fax: 353 21 4901382. E-mail: r.oconnor{at}ucc.ie.

Molecular and Cellular Biology, June 2006, p. 4041-4051, Vol. 26, No. 11
0270-7306/06/$08.00+0     doi:10.1128/MCB.01868-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Legate, K. R., Wickstrom, S. A., Fassler, R. (2009). Genetic and cell biological analysis of integrin outside-in signaling. Genes Dev. 23: 397-418 [Abstract] [Full Text]  
  • Bandyopadhyay, B. C., Ong, H. L., Lockwich, T. P., Liu, X., Paria, B. C., Singh, B. B., Ambudkar, I. S. (2008). TRPC3 Controls Agonist-stimulated Intracellular Ca2+ Release by Mediating the Interaction between Inositol 1,4,5-Trisphosphate Receptor and RACK1. J. Biol. Chem. 283: 32821-32830 [Abstract] [Full Text]  
  • Kiely, P. A., Baillie, G. S., Lynch, M. J., Houslay, M. D., O'Connor, R. (2008). Tyrosine 302 in RACK1 Is Essential for Insulin-like Growth Factor-I-mediated Competitive Binding of PP2A and {beta}1 Integrin and for Tumor Cell Proliferation and Migration. J. Biol. Chem. 283: 22952-22961 [Abstract] [Full Text]  
  • Xia, H., Nho, R., Kleidon, J., Kahm, J., Henke, C. A. (2008). Polymerized Collagen Inhibits Fibroblast Proliferation via a Mechanism Involving the Formation of a {beta}1 Integrin-Protein Phosphatase 2A-Tuberous Sclerosis Complex 2 Complex That Suppresses S6K1 Activity. J. Biol. Chem. 283: 20350-20360 [Abstract] [Full Text]  
  • Gushiken, F. C., Patel, V., Liu, Y., Pradhan, S., Bergeron, A. L., Peng, Y., Vijayan, K. V. (2008). Protein Phosphatase 2A Negatively Regulates Integrin {alpha}IIb{beta}3 Signaling. J. Biol. Chem. 283: 12862-12869 [Abstract] [Full Text]  
  • Hollier, B. G., Kricker, J. A., Van Lonkhuyzen, D. R., Leavesley, D. I., Upton, Z. (2008). Substrate-Bound Insulin-Like Growth Factor (IGF)-I-IGF Binding Protein-Vitronectin-Stimulated Breast Cell Migration Is Enhanced by Coactivation of the Phosphatidylinositide 3-Kinase/AKT Pathway by {alpha}v-Integrins and the IGF-I Receptor. Endocrinology 149: 1075-1090 [Abstract] [Full Text]  
  • Liu, Y. V., Hubbi, M. E., Pan, F., McDonald, K. R., Mansharamani, M., Cole, R. N., Liu, J. O., Semenza, G. L. (2007). Calcineurin Promotes Hypoxia-inducible Factor 1{alpha} Expression by Dephosphorylating RACK1 and Blocking RACK1 Dimerization. J. Biol. Chem. 282: 37064-37073 [Abstract] [Full Text]  
  • Kong, M., Bui, T. V., Ditsworth, D., Gruber, J. J., Goncharov, D., Krymskaya, V. P., Lindsten, T., Thompson, C. B. (2007). The PP2A-associated Protein {alpha}4 Plays a Critical Role in the Regulation of Cell Spreading and Migration. J. Biol. Chem. 282: 29712-29720 [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»