C-TAK1 regulates Ras signaling by phosphorylating the MAPK scaffold, KSR1

Kinase suppressor of Ras (KSR) is a conserved component of the Ras pathway that interacts directly with MEK and MAPK. Here we show that KSR1 transloca tes from the cytoplasm to the cell surface in response to growth factor tre atment and that this process is regulated by Cdc25C-associated kinase 1 (C- TAK1). C-TAK1 constitutively associates with mammalian KSR1 and phosphoryla tes serine 392 to confer 14-3-3 binding and cytoplasmic sequestration of KS R1 in unstimulated cells. In response to signal activation, the phosphoryla tion state of S392 is reduced, allowing the KSR1 complex to colocalize with activated Ras and Raf-1 at the plasma membrane, thereby facilitating the p hosphorylation reactions required for the activation of MEK and MAPK.