Fig. 4. K-Ras4B signaling pathway. K-Ras4B is activated by SOS, a nucleotide exchange factor (GEF), via the GDP-to-GTP exchange and deactivated by NF1, a GTPase-activating protein (GAP) via the GTP-to-GDP hydrolysis (top left panel). Oncogenic driver mutations at the position 12, such as G12D, G12C, and G12V, impair the GAP-mediated hydrolysis and maintain Ras in a constitutively active GTP-bound state (top right panel). In the MAPK pathway, active GTP-bound K-Ras4B proteins recruit Raf to the plasma membrane and lead to Raf activation through dimerization of kinase domains. Active Raf dimers lead to the activation of a series of the MAPK kinases, resulting in cell proliferation. In the PI3K/AKT pathway, K-Ras4B recruits PI3K to the plasma membrane, leading to the production of the signaling lipid PIP₃, which recruits AKT to the membrane, followed by activation by PDK1 and mTORC2. Active AKT is involved in the activation of mTORC1, leading to cell growth. Active-like, GDP-bound K-Ras4B with oncogenic G12V mutation can activate MAPK and PI3K/AKT pathways. The GDP-bound K-Ras4B (middle panel) and GTP-bound K-Ras4B (bottom panel) structures. In surface representation, two distinct conformations correspond to the inactive and active-like structures for K-Ras4B^G12V-GDP, and the inactive-like and active structures for K-Ras4B^WT-GTP. Both K-Ras4B^G12V-GDP and K-Ras4B^WT-GTP exhibit the open and closed Switch I and Switch II conformations. The open and closed switch regions represent K-Ras4B in the inactive and active states, respectively. Abbreviation: RTK, receptor tyrosine kinase; Grb2, growth factor receptor-bound protein 2; SOS, Son of sevenless; NF1, neurofibromin 1, MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; ERK, extracellular signal-regulated kinase; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; mTOR, mammalian target of rapamycin.