KSR2 Is a Calcineurin Substrate that Promotes ERK Cascade Activation in Response to Calcium Signals

Laboratory of Cell and Developmental Signaling, SAIC-Frederick, Inc., National Cancer Institute at Frederick, Frederick, MD 21702, USA.
Molecular cell (Impact Factor: 14.02). 07/2009; 34(6):652-62. DOI: 10.1016/j.molcel.2009.06.001
Source: PubMed


Protein scaffolds have emerged as important regulators of MAPK cascades, facilitating kinase activation and providing crucial spatio/temporal control to their signaling outputs. Using a proteomics approach to compare the binding partners of the two mammalian KSR scaffolds, we find that both KSR1 and KSR2 interact with the kinase components of the ERK cascade and have a common function in promoting RTK-mediated ERK signaling. Strikingly, we find that the protein phosphatase calcineurin selectively interacts with KSR2 and that KSR2 uniquely contributes to Ca2+-mediated ERK signaling. Calcineurin dephosphorylates KSR2 on specific sites in response to Ca2+ signals, thus regulating KSR2 localization and activity. Moreover, we find that depletion of endogenous KSR2 impairs Ca2+-mediated ERK activation and ERK-dependent signaling responses in INS1 pancreatic beta-cells and NG108 neuroblastoma cells. These findings identify KSR2 as a Ca2+-regulated ERK scaffold and reveal a new mechanism whereby Ca2+ impacts Ras to ERK pathway signaling.

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    • "Inhibition of intracellular calcium resulted in a complete inhibition of PGE2 induced Erk1/2 and p38 phosphorylation at BAPTA concentrations greater than 25 µM (Fig. 6A, data not shown). Erk 1/2 could be activated by intracellular calcium through several pathways including calcineurin and calmodulin dependent kinase II (CamKII) [22]–[24]. However, we found that activity of calcineurin in WT and EP3 −/− cells significantly decreased after PGE2 stimulation. "
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    • "These observations reveal ksr2 À/À mice as a useful model for understanding physiological pathways contributing to human obesity and for revealing novel biochemical mechanisms that link obesity to insulin resistance. KSR2 is a scaffold protein in the Raf/MEK/ERK signaling cascade, where it functions along with its paralog, KSR1, to coordinate the interaction of these molecules to facilitate signal transduction and regulate the intensity and duration of ERK signaling (Dougherty et al. 2009). KSR2 also interacts with and promotes activation of the primary regulator of cellular energy homeostasis, AMPK (Costanzo-Garvey et al. 2009; Fernandez et al. 2012). "
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    • "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]. Thus, KSR1 might regulate mTOR activation in T cells, both by controlling ERK activation and by bringing together members of the ERK and the mTOR pathway. "
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