Embryonic patterning events such as neural tube formation are dependent upon graded cellular responses elicited by a gradient of secreted signaling molecules (often referred to as morphogens). The free diffusion of the Wnt and Hedgehog molecules is restricted by lipid adducts that support their graded distribution from producing cells. The lipidation of these proteins can also be essential to biosynthesis as in the case of the Wnt proteins.
We have discovered that the enzymes that mediate the fatty acylation of these proteins are highly druggable and are potential therapeutic targets in cancer. Given that only three protein substrates have been described for the sixteen members of these membrane-bound O-acyltransferases (MBOATs), other therapeutically relevant fatty acylated targets are unknown.
Using techniques we have developed for chemically labeling lipidated proteins coupled with mass spectrometry, we will undertake systematic approaches to identify these other potentially high-value drug targets.