Kirsten rat sarcoma virus proto-oncogene-Rapidly accelerated fibrosarcoma Ras-binding domain interaction (KRAS-RAF-RBD interaction)

The KRAS-RAF-RBD interaction is a pivotal event in the mitogen-activated protein kinase (MAPK) signaling pathway, serving as the primary bridge between upstream Ras activation and downstream kinase cascades (UniProt P01116, P04049). In this interaction, active GTP-bound KRAS recruits RAF kinases, such as BRAF or CRAF, to the plasma membrane by binding to their highly conserved Ras-binding domain (RBD). This membrane recruitment is a prerequisite for RAF dimerization and the subsequent phosphorylation of MEK and ERK, which ultimately promotes cell proliferation, survival, and differentiation. In many human malignancies, including pancreatic and lung cancers, oncogenic KRAS mutations lead to persistent GTP-loading and constitutive activation of this interaction, driving uncontrolled tumor growth. Therapeutic strategies targeting the KRAS-RAF-RBD interface, such as "Ras-mimetics" like Rigosertib, aim to competitively inhibit this protein-protein interaction (PPI) to shut down oncogenic signaling (Athuluri-Divakar et al., 2016). Unlike direct KRAS inhibitors that target specific mutations like G12C, PPI inhibitors of the KRAS-RAF complex have the potential to be effective across a broader range of KRAS variants. However, the development of these inhibitors faces challenges, including the need for high affinity to disrupt the large, relatively flat interface of the RBD and the risk of systemic toxicity due to the pathway's role in normal cell function (Moore et al., 2020). Current research focuses on optimizing the potency of these inhibitors and identifying biomarkers, such as p-ERK levels, to monitor their efficacy in clinical settings.

Other names

KRAS-RAF interactionRas-Raf bindingKRAS-CRAF interactionKRAS-BRAF interactionRas-effector interaction

Inhibition of the protein-protein interaction between active, GTP-bound KRAS and the Ras-binding domain (RBD) of RAF kinases, preventing RAF recruitment to the plasma membrane and subsequent activation of the MAPK/ERK signaling cascade (Athuluri-Divakar et al., 2016; Kessler et al., 2019).