Figure 6. Model of the ADAM17 life cycle.

ADAM17 exists as immature proform (pADAM17) and as mature protease (mADAM17) in cells. After ADAM17 is translated into the ER, it travels iRhom-dependent to the Golgi apparatus, where the maturation takes place. This process seems to be a tightly regulate bottleneck in the life cycle of ADAM17 dividing a big pool of immature from a smaller pool of mature molecules. Most of the mature ADAM17 seems to be intracellularly located whilst only a small amount is actually at the cell surface, where shedding can take place. Stimulation with physiological stimulators of ADAM17-mediated shedding such as Thrombin or Histamine does not alter the amount of cell surface ADAM17 or the overall amount of mature ADAM17 in the cell. Most recently it was shown, that most of the mature ADAM17 at the cell surface is internalised and recycled. The non-physiological PKC-activator PMA does not only activate ADAM17-mediated shedding but does also drastically dysregulate the localisation of mature ADAM17. PMA leads to a fast increase in surface expression followed by internalisation and lysosomal degradation of ADAM17. The activation of this path eventually empties the pool of mature ADAM17 within a few hours without affecting the pool of immature ADAM17.