Endocytic Control of Cell‐Autonomous and Non‐Cell‐Autonomous Functions of p53
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.
Authors
- Vittoria Matafora (ORCID: https://orcid.org/0000-0002-4311-998X)
- Letizia Lanzetti (ORCID: https://orcid.org/0000-0001-7541-5524)
- Elena Zaccheroni (ORCID: https://orcid.org/0000-0002-0161-9804)
- Giuseppe Ciossani (ORCID: https://orcid.org/0000-0001-5293-4292)
- Luigi Scietti (ORCID: https://orcid.org/0000-0001-8691-9429)
- Stefano Freddi (ORCID: https://orcid.org/0000-0003-4263-3060)
- Alessandro Cuomo (ORCID: https://orcid.org/0000-0002-9778-7190)
- Simona Ronzoni (ORCID: https://orcid.org/0000-0002-3976-3406)
- Rosalind H. Gunby (ORCID: https://orcid.org/0000-0002-4359-3884)
- Salvatore Pece (ORCID: https://orcid.org/0000-0003-1764-3929)
- Ivan Nicola Colaluca (ORCID: https://orcid.org/0000-0002-3371-112X)
- C. Zucca (ORCID: https://orcid.org/0000-0002-0701-5227)
- Sara Sigismund (ORCID: https://orcid.org/0000-0002-1396-4453)
- Simone Pelicci (ORCID: https://orcid.org/0000-0003-3539-8613)
- Roberta Cacciatore
- Irene Schiano Lomoriello
- Pier Paolo Di Fiore
- Andrea Basile
- Angela Bachi
- Mario Faretta
- Giuliana Pelicci
Institutions
- Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT)
- University of Milan (IT)
- IFOM (IT)
- Torino e-district (IT)
- Department of Medical Sciences (BY)
- Candiolo Cancer Institute (IT)
- University of Turin (IT)
- European Institute of Oncology (IT)
Publication Details
- Journal
- Advanced Science
- Published
- 2026-01-30
- DOI
- https://doi.org/10.1002/advs.202513765
- Primary Topic
- Cellular transport and secretion
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Ministero della Salute
- Università degli Studi di Pavia
- Associazione Italiana per la Ricerca sul Cancro