Meta-Biol

• Pathways

KSR1 (Kinase suppressor of RAS 1) was originally identified in Drosophila and C. elegans as a suppressor of activated RAS, and is one of a number of scaffolding proteins that bring RAS-RAF-MAPK members together to promote pathway activation (Therrien et al, 1995; Kornfeld et al, 1995; Sundaram et al, 1995; reviewed in Zhang et al, 2013). Consistent with its role as a scaffolding protein, KSR1 interacts with all of the kinases of the MAPK pathway. Interaction with the MEK proteins MAP2K1 and MAP2K2 is constitutive, while pathway activation promotes heterodimerization with activated RAF proteins and subsequent interaction with ERK/MAPK proteins (Rajakulendran et al, 2009; Therrien et al, 1996; McKay et al, 2009; Hu et al, 2011; Hu et al, 2013; Brennan et al, 2011; note, however, that for simplicity MAP2K/MEK proteins are not depicted as part of this reaction).
Like the RAF proteins, KSR1 is maintained in an inactive state in quiescent cells by interaction with 14-3-3 dimers; this interaction is promoted by phosphorylation of KSR1 residues S311 and S406 by the MAP/microtubule affinity-regulating kinase 3 (MARK3), which is constitutively bound to KSR1 (Muller et al, 2001).