fig1

Figure 1. RTK-Ras-MAPK signaling, BRAF mutants and HDAC influence. Binding to the corresponding growth factor activates the RTK, leading to receptor dimerization and autophosphorylation. Docking and adapter proteins (Grb2-SOS complex) recognize and bind the phosphorylated RTK, whereupon farnesylated Ras is activated. Ras activates RAF, which dimerizes and phosphorylates MEKs, followed by phosphorylation of MAPKs (JNK, p38) and/or ERKs. Activated MAPK/ERK upregulated oncogenic transcription factors (e.g., c-Jun, c-Fos, and c-Myc), which promote cell proliferation and survival. HDACs regulate gene transcription. Mutant BRAFs (class I BRAF^V600 monomers, class II BRAF^nonV600 homodimers, and class III BRAF^nonV600-CRAF heterodimers) activate MAPK signaling in uncontrolled/dysregulated ways. ERK: Extracellular signal-regulated kinase; Grb2: growth factor receptor-bound protein 2; HDAC: histone deacetylase; JNK: c-Jun kinase; MAPK: mitogen-activated protein kinase; MEK: MAPK/ERK kinase; RAF: rapidly accelerated fibrosarcoma; Ras: rat sarcoma; RTK: receptor tyrosine kinase; SOS: son of sevenless; BRAF: B-Raf, B-rapidly accelerated fibrosarcoma.