KSR-1 is a scaffold protein that is essential for Ras-induced activation of the 
highly conserved RAF-MEK-ERK kinase module. Previously, we identified a close 
homolog of KSR-1, called KSR-2, through structural homology-based data mining. 
In order to further understand the role of KSR-2 in MAPK signaling, we undertook 
a functional proteomics approach to elucidate the dynamic composition of the 
KSR-2 functional complex in HEK-293 cells under conditions with and without 
TNF-alpha stimulation. We found nearly 100 proteins that were potentially 
associated with KSR-2 complex and 43 proteins that were likely recruited to the 
super molecular complex after TNF-alpha treatment. Our results indicate that 
KSR-2 may act as a scaffold protein similar as KSR-1 to mediate the MAPK core 
(RAF-MEK-ERK) signaling but with a distinct RAF isoform specificity, namely 
KSR-2 may only mediate the A-RAF signaling while KSR-1 is responsible for 
transducing signals only from c-RAF. In addition, KSR-2 may be involved in the 
activation of many MAPK downstream signaling molecules such as p38 MAPK, IKAP, 
AIF, and proteins involved in ubiquitin-proteasome, apoptosis, cell cycle 
control, and DNA synthesis and repair pathways, as well as mediating crosstalks 
between MAPK and several other signaling pathways, including PI3K and insulin 
signaling. While interactions with these molecules are not known for KSR-1, it's 
reasonable to hypothesize that KSR-1 may also play a similar role in mediating 
these downstream signaling pathways.