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.