Endocytic Control of Cell‐Autonomous and Non‐Cell‐Autonomous Functions of p53

ABSTRACT NUMB is an endocytic protein with tumor suppressor activity, largely mediated by its ability to inhibit p53 degradation. This function depends on the inclusion of a short alternatively spliced exon (Ex3) in NUMB, although the mechanistic link between endocytosis and p53 regulation remains unclear. Here, we show that the Ex3‐encoded sequence directs NUMB to the plasma membrane, where it forms a complex with the endocytic adaptor SNX9. This complex recruits p53 in an SNX9‐dependent manner and is internalized and trafficked to multivesicular bodies, culminating in exosomal secretion, in a process requiring both SNX9 and NUMB. Exosomal p53 is taken up by recipient cells and translocated to the nucleus, where it activates p53‐dependent transcriptional and phenotypic programs. These findings suggest that exosome‐mediated p53 transfer may contribute to the establishment of a tumor‐suppressive microenvironment.