RTK/Ras/MapK signaling

Receptor tyrosine kinases (RTKs) are a class of membrane-spanning proteins that dimerize when a dimer signaling molecule binds the extracellular receptor domain. When two RTKs dimerize, they autophosphorylation on multiple tyrosine residues. The adaptor protein GRB2 binds to a phosphorylated tyrosine via its SH2 domain. Ras is anchored to the lipid bilayer and is a kinase for many downstream growth pathways. SOS is a Ras-GEF, so upon binding Ras, changes its conformation to have less affinity for GDP and more for GTP so it can get a phosphate group and phosphorylate things such as the Map kinases. The RTK/Ras/MapK pathway has been implicated at multiple points to be overactive in cancer. Drugs such as dacomitinib work to irreversibly bind cystines in the ATP binding kinase domain of the RTK. However, secondary driver mutations often arise in downstream targets such as Ras, rendering treatment of the RTK useless in treating cancer.