Review: Precision medicine and driver mutations: Computational methods, functional assays and conformational principles for interpreting cancer drivers
Fig 10
A general scheme of cell-signaling pathway.
Representatives shown for the MAPK, PI3K/Akt, and Wnt pathways. In the MAPK pathway, Ras gets activated in the presence of the EGFR signal and forms nanoclusters that promote Raf dimerization. Autophosphorylated, active Raf dimer phosphorylates and activatesMEK 1/2, and subsequently phosphorylates and activates ERK 1/2, leading to cell proliferation. In the PI3K/Akt pathway, both Ras and RTK activate PI3K, recruiting it to the plasma membrane, where PI3K phosphorylates PIP2 to produce PIP3. The tumor suppressor PTEN can reverse the PIP3 production. PIP3 recruits both PDK and Akt to the plasma membrane, where PDK and mTORC2 activate Akt, and active Akt phosphorylates the mTORC1, leading to cell growth. The canonical Wnt pathway involves an accumulation of β-catenin in the cytoplasm and translocates β-catenin to the nucleus where it binds to TCF/LEF transcription factors. β-catenin upregulates c-Myc. In the noncanonical Wnt pathway, CaM-bound CaMKII interfere with the canonical β-catenin/TCF/LEF signaling. CaM, Ca2+-calmodulin; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; MAPK, Raf/MEK/ERK; MEK, MAPK kinase; mTORC1, mTOR complex 1; mTORC2, mTOR complex 2; PDK, phosphoinositide-dependent protein kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-bisphosphate; PTEN, phosphatase and tensin homolog; RTK, receptor tyrosine kinase; TCF/LEF, T-cell factor/lymphoid enhancing factor.