What question did this study set out to answer?

The aim is to explore how the endocytic protein NUMB regulates p53 activity and its implications for tumor suppression.

February 2, 2026Advanced Science0 citationsOpen Access

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

RCRoberta Cacciatore ABAndrea Basile SFStefano Freddi

Key Points

The aim is to explore how the endocytic protein NUMB regulates p53 activity and its implications for tumor suppression.
Investigated the role of Ex3 in directing NUMB to the plasma membrane.
Examined the interaction between NUMB and SNX9.
Performed analyses on the internalization and trafficking of p53 to multivesicular bodies.
Assessed the effects of exosomal p53 on recipient cells' transcriptional activity.
NUMB directs p53 to the plasma membrane via its Ex3 sequence.
The NUMB-SNX9 complex facilitates the internalization of p53.
Exosomal p53 is taken up by other cells and activates p53-dependent programs, suggesting a tumor-suppressive effect.

Abstract

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.

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