KIDs rule: regulatory phosphorylation of RTKs

Receptor tyrosine kinases (RTKs) are mediators of multiple cell signaling networks linked to cell growth and differentiation. In general, they exhibit similar overall structure with a ligand-binding extracellular domain and a conserved intracellular tyrosine kinase domain. In many RTKs, the kinase domain is interrupted by a sequence known as the kinase insert domain (KID). In addition to phosphorylation sites within the kinase domain, regulatory phosphorylation also occurs within the KID of several RTKs important in human health and disease. Phosphorylation of specific Tyr or Ser residues within the KID of some RTKs triggers distinct cellular signaling outcomes. Here, we review the functionality of KIDs throughout all RTK families, and provide justification for further study of this often-overlooked domain.