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.

Download full-text


Available from: Andrey Shaw, Oct 08, 2015
17 Reads
  • Source
    • "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 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Simplified representations can be powerful. Two common examples are sequence logos and ribbon diagrams. Both have been extraordinarily successful in capturing complex static features of sequences and structures. Capturing function is challenging, since activation involves triggered dynamic shifts between ON and OFF states. Here, we show that simple funnel drawings can capture and usefully portray proteins by their cellular triggering mechanism. The funnel shape around the proteins' native states can describe mechanisms of upstream signal integration and downstream response. "Function diagrams" are important: they can combine diverse biochemical data to visually distinguish among activation (or recruitment) mechanisms and tag proteins in cellular networks, clarifying their mechanism at a glance. We create templates for function classification and suggest that they can extend signaling pathway maps. Of note, the diagrams describe free energy landscapes; thus, they can be quantified. We name our dynamic free-energy diagrams dFEDs.
    Chemistry & biology 02/2014; 21(3). DOI:10.1016/j.chembiol.2013.12.015 · 6.65 Impact Factor
  • Source
    • "Previous work in our laboratory showed that kinase suppressor of Ras 1 (KSR1), a scaffold protein for Raf, MEK and ERK [18], plays a critical role in the optimal activation of ERK in T cells [16], [17], [19]. Furthermore, KSR1 is known to associate with mTOR, Raptor and Rictor in cycling 293T cells [20]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The mammalian target of rapamycin (mTOR) kinase is a critical regulator of the differentiation of helper and regulatory CD4+ T cells, as well as memory CD8+ T cells. In this study, we investigated the role of the ERK signaling pathway in regulating mTOR activation in T cells. We showed that activation of ERK following TCR engagement is required for sustained mTOR complex 1 (mTORC1) activation. Absence of kinase suppressor of Ras 1 (KSR1), a scaffold protein of the ERK signaling pathway, or inhibition of ERK resulted in decreased mTORC1 activity following T cell activation. However, KSR1-deficient mice displayed normal regulatory CD4+ T cell development, as well as normal memory CD8+ T cell responses to LCMV and Listeria monocytogenes infection. These data indicate that despite its role in mTORC1 activation, KSR1 is not required in vivo for mTOR-dependent T cell differentiation.
    PLoS ONE 02/2013; 8(2):e57137. DOI:10.1371/journal.pone.0057137 · 3.23 Impact Factor
  • Source
    • "Several receptor–ligand interactions between T cells and APCs are important for activation, however activation differences between T cells are determined by whether TCR recognizes the foreign peptide loaded onto the MHC molecule. Interestingly, T cell activation has been shown to be digital in nature: a T cell can only exist in an “Off” (resting) state or an “On” (activated) state (Altan-Bonnet and Germain, 2005; Daniels et al., 2006; Chakraborty et al., 2009; Das et al., 2009; Lin et al., 2009; Prasad et al., 2009). This means that as long as the threshold of activation is achieved, relatively weak stimuli (low affinity) will induce the same response as strong stimuli (high affinity) at the single cell level. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Evolution is often characterized as a process involving incremental genetic changes that are slowly discovered and fixed in a population through genetic drift and selection. However, a growing body of evidence is finding that changes in the environment frequently induce adaptations that are much too rapid to occur by an incremental genetic search process. Rapid evolution is hypothesized to be facilitated by mutations present within the population that are silent or "cryptic" within the first environment but are co-opted or "exapted" to the new environment, providing a selective advantage once revealed. Although cryptic mutations have recently been shown to facilitate evolution in RNA enzymes, their role in the evolution of complex phenotypes has not been proven. In support of this wider role, this paper describes an unambiguous relationship between cryptic genetic variation and complex phenotypic responses within the immune system. By reviewing the biology of the adaptive immune system through the lens of evolution, we show that T cell adaptive immunity constitutes an exemplary model system where cryptic alleles drive rapid adaptation of complex traits. In naive T cells, normally cryptic differences in T cell receptor reveal diversity in activation responses when the cellular population is presented with a novel environment during infection. We summarize how the adaptive immune response presents a well studied and appropriate experimental system that can be used to confirm and expand upon theoretical evolutionary models describing how seemingly small and innocuous mutations can drive rapid cellular evolution.
    Frontiers in Genetics 02/2012; 3:5. DOI:10.3389/fgene.2012.00005
Show more