Ras-Raf-GRB2-SOS signaling axis (Ras/Raf/GRB2/SOS)

The Ras/Raf/GRB2/SOS signaling axis is a fundamental signal transduction module that relays extracellular growth signals from receptor tyrosine kinases (RTKs) to downstream effector cascades, primarily the MAPK/ERK pathway [1.4.1, 1.4.3]. Upon activation of an RTK, the adaptor protein Growth factor receptor-bound protein 2 (GRB2) is recruited to the receptor's phosphorylated tyrosine residues, which then brings the guanine nucleotide exchange factor Son of Sevenless (SOS) to the plasma membrane [1.4.2]. SOS facilitates the conversion of the small GTPase Ras from its inactive GDP-bound state to its active GTP-bound state [1.4.2]. Active Ras subsequently recruits and activates Raf kinases (A-Raf, B-Raf, or C-Raf), initiating a phosphorylation relay that ultimately regulates gene expression related to cell proliferation, differentiation, and survival [1.4.3]. Mutations in components of this axis, particularly KRAS and BRAF, are among the most frequent drivers of human malignancies, including lung, colorectal, and pancreatic cancers [1.3.4]. Consequently, this axis is a major focus of oncology drug development, with approved therapies targeting specific mutant nodes like KRAS G12C and BRAF V600E, as well as investigational agents targeting the protein-protein interactions between GRB2 and SOS [1.2.1, 1.3.4].

Other names

Ras-MAPK pathwayMAPK/ERK signaling axisRTK-Ras-Raf-MEK-ERK pathwayRas/Raf/GRB2/SOS pathway

Drugs targeting this axis operate through several distinct mechanisms: covalent inhibition of specific mutant GTPases (e.g., KRAS G12C), competitive inhibition of the ATP-binding site in Raf kinases, and disruption of protein-protein interactions (PPIs) such as the GRB2-SOS1 or SOS1-Ras interfaces to prevent membrane recruitment and activation of the pathway [1.2.1, 1.3.2, 1.3.4].