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 Eblen, S. T.
Right arrow Articles by Catling, A. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Eblen, S. T.
Right arrow Articles by Catling, A. D.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, March 2004, p. 2308-2317, Vol. 24, No. 6
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.6.2308-2317.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Mitogen-Activated Protein Kinase Feedback Phosphorylation Regulates MEK1 Complex Formation and Activation during Cellular Adhesion

Scott T. Eblen,* Jill K. Slack-Davis, Adel Tarcsafalvi, J. Thomas Parsons, Michael J. Weber, and Andrew D. Catling{dagger}

Department of Microbiology, School of Medicine, University of Virginia, Charlottesville, Virginia 22908

Received 11 November 2003/ Accepted 17 December 2003

Cell adhesion and spreading depend on activation of mitogen-activated kinase, which in turn is regulated both by growth factor and integrin signaling. Growth factors, such as epidermal growth factor, are capable of activating Ras and Raf, but integrin signaling is required to couple Raf to MEK and MEK to extracellular signal-regulated protein kinase (ERK). It was previously shown that Rac-p21-activated kinase (PAK) signaling regulated the physical association of MEK1 with ERK2 through phosphorylation sites in the proline-rich sequence (PRS) of MEK1. It was also shown that activation of MEK1 and ERK by integrins depends on PAK phosphorylation of S298 in the PRS. Here we report a novel MEK1-specific regulatory feedback mechanism that provides a means by which activated ERK can terminate continued PAK phosphorylation of MEK1. Activated ERK can phosphorylate T292 in the PRS, and this blocks the ability of PAK to phosphorylate S298 and of Rac-PAK signaling to enhance MEK1-ERK complex formation. Preventing ERK feedback phosphorylation on T292 during cellular adhesion prolonged phosphorylation of S298 by PAK and phosphorylation of S218 and S222, the MEK1 activating sites. We propose that activation of ERK during adhesion creates a feedback system in which ERK phosphorylates MEK1 on T292, and this in turn blocks additional S298 phosphorylation in response to integrin signaling.

* Corresponding author. Mailing address: Department of Microbiology, P.O. Box 800734, Rm. 216 Jordan Hall, University of Virginia, Charlottesville, VA 22908. Phone: (434) 924-8710. Fax: (434) 982-0689. E-mail: ste4n{at}virginia.edu.

{dagger} Present address: Department of Pharmacology and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70115.

Molecular and Cellular Biology, March 2004, p. 2308-2317, Vol. 24, No. 6
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.6.2308-2317.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Niault, T., Sobczak, I., Meissl, K., Weitsman, G., Piazzolla, D., Maurer, G., Kern, F., Ehrenreiter, K., Hamerl, M., Moarefi, I., Leung, T., Carugo, O., Ng, T., Baccarini, M. (2009). From autoinhibition to inhibition in trans: the Raf-1 regulatory domain inhibits Rok-{alpha} kinase activity. JCB 187: 335-342 [Abstract] [Full Text]  
  • Nadeau, V., Guillemette, S., Belanger, L.-F., Jacob, O., Roy, S., Charron, J. (2009). Map2k1 and Map2k2 genes contribute to the normal development of syncytiotrophoblasts during placentation. Development 136: 1363-1374 [Abstract] [Full Text]  
  • Shin, S.-Y., Rath, O., Choo, S.-M., Fee, F., McFerran, B., Kolch, W., Cho, K.-H. (2009). Positive- and negative-feedback regulations coordinate the dynamic behavior of the Ras-Raf-MEK-ERK signal transduction pathway. J. Cell Sci. 122: 425-435 [Abstract] [Full Text]  
  • Skarpen, E., Flinder, L. I., Rosseland, C. M., Orstavik, S., Wierod, L., Oksvold, M. P., Skalhegg, B. S., Huitfeldt, H. S. (2008). MEK1 and MEK2 regulate distinct functions by sorting ERK2 to different intracellular compartments. FASEB J. 22: 466-476 [Abstract] [Full Text]  
  • Jimenez-Sanchez, M., Cid, V. J., Molina, M. (2007). Retrophosphorylation of Mkk1 and Mkk2 MAPKKs by the Slt2 MAPK in the Yeast Cell Integrity Pathway. J. Biol. Chem. 282: 31174-31185 [Abstract] [Full Text]  
  • Szczur, K., Xu, H., Atkinson, S., Zheng, Y., Filippi, M.-D. (2006). Rho GTPase CDC42 regulates directionality and random movement via distinct MAPK pathways in neutrophils. Blood 108: 4205-4213 [Abstract] [Full Text]  
  • Joly, D., Ishibe, S., Nickel, C., Yu, Z., Somlo, S., Cantley, L. G. (2006). The Polycystin 1-C-terminal Fragment Stimulates ERK-dependent Spreading of Renal Epithelial Cells. J. Biol. Chem. 281: 26329-26339 [Abstract] [Full Text]  
  • Shi, G.-X., Han, J., Andres, D. A. (2005). Rin GTPase Couples Nerve Growth Factor Signaling to p38 and b-Raf/ERK Pathways to Promote Neuronal Differentiation. J. Biol. Chem. 280: 37599-37609 [Abstract] [Full Text]  
  • Tarrega, C., Rios, P., Cejudo-Marin, R., Blanco-Aparicio, C., van den Berk, L., Schepens, J., Hendriks, W., Tabernero, L., Pulido, R. (2005). ERK2 Shows a Restrictive and Locally Selective Mechanism of Recognition by Its Tyrosine Phosphatase Inactivators Not Shared by Its Activator MEK1. J. Biol. Chem. 280: 37885-37894 [Abstract] [Full Text]  
  • Pullikuth, A., McKinnon, E., Schaeffer, H.-J., Catling, A. D. (2005). The MEK1 Scaffolding Protein MP1 Regulates Cell Spreading by Integrating PAK1 and Rho Signals. Mol. Cell. Biol. 25: 5119-5133 [Abstract] [Full Text]  
  • Slice, L. W., Chiu, T., Rozengurt, E. (2005). Angiotensin II and Epidermal Growth Factor Induce Cyclooxygenase-2 Expression in Intestinal Epithelial Cells through Small GTPases Using Distinct Signaling Pathways. J. Biol. Chem. 280: 1582-1593 [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»