Receptor tyrosine kinases (RTKs) have been demonstrated to signal via regulated 
intramembrane proteolysis, in which ectodomain shedding and subsequent 
intramembrane cleavage by gamma-secretase leads to release of a soluble 
intracellular receptor fragment with functional activity. For most RTKs, 
however, it is unknown whether they can exploit this new signaling mechanism. 
Here we used a system-wide screen to address the frequency of susceptibility to 
gamma-secretase cleavage among human RTKs. The screen covering 45 of the 55 
human RTKs identified 12 new as well as all nine previously published 
gamma-secretase substrates. We biochemically validated the screen by 
demonstrating that the release of a soluble intracellular fragment from 
endogenous AXL was dependent on the sheddase disintegrin and metalloprotease 10 
(ADAM10) and the gamma-secretase component presenilin-1. Functional analysis of 
the cleavable RTKs indicated that proliferation promoted by overexpression of 
the TAM family members AXL or TYRO3 depends on gamma-secretase cleavage. Taken 
together, these data indicate that gamma-secretase-mediated cleavage provides an 
additional signaling mechanism for numerous human RTKs.