FIGURE 4

Overview of the RAS Signaling Pathway. The Ras signaling cascade is stimulated by the binding of a growth factor/cytokine to the appropriate RTK. C-CBL (Casitas B-lineage lymphoma) is an E3 ubiquitin ligase responsible for the ubiquitination of RTKs leading to their internalization and degradation. The activated receptor binds the adaptor proteins GRB2 (growth factor receptor bound protein 2) and SHP2/PTPN11 (protein tyrosine phosphatase non-receptor type 11) and recruits SOS1 (son of sevenless homolog 1). SOS1 facilitates the conversion of RAS from its inactive to active confirmation through the binding of GTP. RAS-GTP activates RAF, PI3K, and adenylate cyclase to cause a signaling cascade. RAF activates MEK which in turn activates ERK. Adenylate cyclase facilitates the production of cAMP which ultimately activates PKA. Activated ERK and PKA are protein kinases that translocate to the nucleus where they phosphorylate and activate transcription factors (TF) which drive the transcription of target genes involved in proliferation, cell growth, and differentiation. PI3K activates AKT which can activate mTOR and inhibit p53, leading to the inhibition of apoptosis. This figure was generated using information from several research articles and reviews (Ries et al., 2000; Kratz et al., 2006; Malaquias and Jorge, 2014; Wang et al., 2018).