Receptor tyrosine kinases or RTKs are membrane-bound receptors that phosphorylate specific tyrosine on protein substrates. RTKs regulate cellular growth, differentiation, survival, and migration. They contain an extracellular ligand binding domain, a transmembrane domain, and a cytosolic tail with intrinsic kinase activity. Several extracellular signaling molecules activate RTKs in one or more ways and relay the signal downstream. Ligands such as platelet-derived growth factor (PDGF) or colony-stimulating factor-1 (CSF-1) with two receptor-binding sites bind RTKs simultaneously and induce ligand-mediated dimerization.

In contrast, epidermal growth factor (EGF) and some other ligands activate the RTKs by receptor-mediated dimerization. Monomeric ligands with a single receptor binding site bind RTKs and induce conformational changes in the extracellular domain of RTK. This exposes the receptor dimerization interface and accelerates receptor-mediated dimerization.

Receptor dimerization places the cytoplasmic kinase domain together. It induces trans-autophosphorylation, where the kinase domain of one monomer phosphorylates the tyrosine on the activation loop of the cytoplasmic tail of the second RTK and vice versa. Once phosphorylated, the activation loop is pulled away and stabilized at the position that exposes the substrate protein-binding region and ATP entry. This activates the kinase domain, allowing RTKs to phosphorylate intracellular signaling proteins. For example, proteins with Src homology 2 (SH2) or phospho-tyrosine binding (PTB) domains bind specific phosphotyrosine residues on RTKs to get phosphorylated and activated by RTKs.

The phosphotyrosines on RTKs also induce RTK inhibition. They are a binding site for Cbl, an SH2 domain-containing protein that causes ubiquitin-mediated receptor degradation, which switches off RTK signaling.