Proteolytic cleavages give receptor tyrosine kinases the gift of ubiquity

Receptor tyrosine kinases (RTK) constitute a large family of membrane receptors which, in response to their respective ligand, transmit information into cells. RTK regulate multiple biological responses, and their deregulation is often associated with tumourigenesis. The intracellular signalling pathways initiated by full-length membrane RTK are studied extensively, but many RTK fragments showing unexpected cellular localization have been observed. These fragments are generated by proteolytic cleavages, catalyzed notably by caspases, membrane metalloproteases or gamma-secretase. Interestingly, these cleavages, in addition to regulating membrane receptor levels, generate active fragments that can regulate biological processes, such as transcription or the survival/apoptosis balance. Thus, proteolytic cleavages release RTK from the membrane and extend their functions. Furthermore, the RTK proteolysis are involved in regulating cell transformation, which highlights their potential as attractive targets for therapeutic strategies. Oncogene (2009) 28, 2185-2195; doi: 10.1038/onc.2009.88; published online 4 May 2009