Figure 2

Structure of the mammalian Ras pathway (A) and distribution of selective pressures across the upstream/downstream pathway axis (B). (A) Upon binding to mitogenic ligands (e.g. EGF), receptor tyrosine kinases (RTKs, e.g. EGFR), are able to recruit Grb2 to the cell membrane. Grb2 binds to SOS proteins, thus promoting their membrane location. Once in the membrane, SOS proteins act as guanine exchange factors of Ras proteins, thereby promoting Ras’ activation. Activated forms of Ras promote the recruitment of Raf proteins to the membrane, which in turn phosphorylate MEK proteins. Activated MEK proteins then phosphorylate ERK proteins. The required molecular interactions for these phosphorylation events are facilitated by interaction with the scaffold proteins KSR. Finally, ERK proteins phosphorylate RSK proteins, which in turn activate ribosomal protein S6 and a number of transcription factors, thus promoting cell proliferation, differentiation, migration and survival, and modulating cellular metabolism. (B) Correlation between the position of genes in the pathway (defined as the number of steps required for the signal transduction between RTKs to each of the genes in the pathway) and their rates of evolution. See Additional file 1: Table S5 for a full list of the core pathway genes and their rates of evolution.