Fig. 9. Schematic representation of proAR intracellular trafficking. Without TPA stimulation, proAR primarily localizes at the plasma membrane. TPA induces partial proAR-ectodomain shedding, resulting in the production of a soluble growth factor (AR) and a C-terminal fragment (AR-CTF). In addition, TPA causes the endocytosis of both AR-CTF and the residual un-shed proAR. AR-CTF then translocates to the lysosome (black arrow) and un-shed proAR trafficks to the INM (red arrow). During translocation to the INM, proAR is truncated at the C-terminus, and targeted to the ER. Subsequently ER-localized proAR diffuses or is actively transported to the INM, where it is tethered via interaction with A-type lamin and downregulates global transcription. PM, plasma membrane.