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

Department of Pathology and Immunology, Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 03/2009; 29(8):2082-91. DOI: 10.1128/MCB.01634-08
Source: PubMed


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.

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    • "The MAPK system also shows that the mechanism type is tuned to the signaling module: the two-state cooperative irreversible responses were adopted for processes such as cell-cycle progression , neuronal differentiation, T cell selection, and cell fate (Aoki et al., 2011; Ferrell and Machleder, 1998; Lin et al., 2009; Xiong and Ferrell, 2003); graded response over a wide range of threshold doses was adopted for signaling, including activation by different inputs (Takahashi and Pryciak, 2008). Furthermore, tethering to a scaffold, as in the case of MEK and ERK to KSR, can suppress phosphorylation and thereby inhibit digital Figure 3 "
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