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Molecular and Cellular Biology, April 2009, p. 2082-2091, Vol. 29, No. 8
0270-7306/09/$08.00+0     doi:10.1128/MCB.01634-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

KSR1 Modulates the Sensitivity of Mitogen-Activated Protein Kinase Pathway Activation in T Cells without Altering Fundamental System Outputs{triangledown}

Joseph Lin,1*,{dagger} Angus Harding,2*,{dagger} Emanuele Giurisato,1 and Andrey S. Shaw1

Department of Pathology and Immunology, Howard Hughes Medical Institute, Washington University School of Medicine, 660 S. Euclid, Box 8118, St. Louis, Missouri 63110,1 Queensland Brain Institute, University of Queensland, QBI Building 79, St. Lucia, Queensland 4072, Australia2

Received 20 October 2008/ Returned for modification 2 December 2008/ Accepted 22 January 2009

Mitogen-activated protein kinase (MAPK) cascades are evolutionarily conserved signaling pathways that regulate cell fate decisions. They generate a wide range of signal outputs, including graded and digital responses. In T cells, MAPK activation is digital in response to T-cell-receptor stimulation; however, whether other receptors on T cells that lead to MAPK activation are graded or digital is unknown. Here we evaluate MAPK activation in T cells at the single-cell level. We show that T cells responded digitally to stimulation with superantigen-loaded antigen-presenting cells, whereas they responded in a graded manner to the chemokine SDF-1, demonstrating that the system output of the MAPK module is highly plastic and determined by components upstream of the MAPK module. These findings also confirm that different MAPK system outputs are used by T cells to control discrete biological functions. Scaffold proteins are essential for proper MAPK signaling and function as they physically assemble multiple components and regulators of MAPK cascades. We found that the scaffold protein KSR1 regulated the threshold required for MAPK activation in T cells without affecting the nature of the response. We conclude that KSR1 plays a central role in determining the sensitivity of T-cell responses and is thus well positioned as a key control point.

* Corresponding author. Mailing address for Joseph Lin: Department of Pathology and Immunology, Howard Hughes Medical Institute, Washington University School of Medicine, 660 S. Euclid, Box 8118, St. Louis, MO 63110. Phone: (314) 362-4601. Fax: (314) 362-8888. E-mail: jlin1{at}pathbox.wustl.edu. Mailing address for Angus Harding: Queensland Brain Institute, University of Queensland, QBI Building 79, St. Lucia, Queensland 4072, Australia. Phone: (61) 7-3346- 6300. Fax: (61) 7-3346-6301. E-mail: a.harding1{at}uq.edu.au

{triangledown} Published ahead of print on 2 February 2009.

{dagger} J.L. and A.H. contributed equally to this study.

Molecular and Cellular Biology, April 2009, p. 2082-2091, Vol. 29, No. 8
0270-7306/09/$08.00+0     doi:10.1128/MCB.01634-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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