Figure 2: RAF and KSR proteins within the RAS–ERK pathway.
a | Primary structure highlights the domain architecture of mammalian RAF proteins (ARAF, BRAF and CRAF) and their kinase suppressor of RAS (KSR; KSR1 and KSR2) paralogues. The common structure of the viral oncoproteins v-RAF and v-MIL is also depicted. Viral oncoproteins have amino-terminal truncations compared to their cellular homologues and are fused to the N-myristoylated (N-myr) viral Gag protein. RAF proteins are composed of three conserved regions (CR1–CR3), and KSR proteins comprise five conserved areas (CA1–CA5). The schematic shows the relative positions of RAS-binding domain (RBD), Cys-rich domain (CRD), Ser/Thr-rich sequences, kinase domains, BRAF-specific region (BRS)244, coiled-coil sterile α-motif (CC-SAM) and Pro-rich sequence. b | Core components of a typical RAS–ERK signalling cascade are depicted. Incoming signals in the form of ligand-activated receptor Tyr kinases (RTKs) activate RAS. RAF and KSR family members form a network of interacting kinases (dashed lines) that are regulated by activated RAS, as well as by a network of peripheral protein–protein interactions and key phosphorylation–dephosphorylation events. Activated RAF phosphorylates MEK on two key Ser residues (Ser218 and Ser222 in human MEK1, and Ser222 and Ser226 in human MEK2), which in turn activates ERK by causing dual phosphorylation of its activation segment (Thr202 and Tyr204 of human ERK1, and Thr185 and Tyr187 of human ERK2). Phosphorylation sites depicted are those found in MEK1 and ERK1. Upon activation, ERK phosphorylates a wide range of targets that can elicit various cellular responses, including growth, proliferation, differentiation, survival and migration.
