TBC1D22B Regulates ER‐to‐Golgi Trafficking via RAB1B Inactivation and Promotes Oncogenic Programs in Breast Cancer
TBC1D22B is a GTPase-activating protein (GAP) associated with poor prognosis in breast cancer (BC). Using complementary proximity-labeling and co-immunoprecipitation proteomics, the TBC1D22B interactome in BC cells is defined, revealing strong enrichment in components of the ER-to-Golgi trafficking machinery, endosomal transport, and adhesion-related pathways. Functional assays, using the Retention Using Selective Hooks (RUSH) system, demonstrate that TBC1D22B inhibits ER-to-Golgi transport in a GAP-dependent manner. Mechanistic studies identify RAB1B as a direct target of TBC1D22B, and RAB1B silencing phenocopies the trafficking defects caused by TBC1D22B overexpression. In 3D culture, TBC1D22B promotes spheroid growth in a manner dependent on its GAP activity and not replicated by its paralog TBC1D22A. Transcriptomic profiling reveals that TBC1D22B overexpression triggers repression of a core module of extracellular matrix and adhesion-related genes, consistent with altered secretory activity. Importantly, this transcriptional program is also evident in primary Luminal BC with high TBC1D22B expression, highlighting a conserved and functionally relevant signature. Together, these findings establish TBC1D22B as a regulator of ER-to-Golgi trafficking via RAB1B and implicate it in oncogenic transcriptional remodeling and tumor growth.
Authors
- Letizia Lanzetti (ORCID: https://orcid.org/0000-0001-7541-5524)
- Giulia Villari (ORCID: https://orcid.org/0000-0002-4811-3990)
- Stefano Freddi (ORCID: https://orcid.org/0000-0003-4263-3060)
- Alessandro Cuomo (ORCID: https://orcid.org/0000-0002-9778-7190)
- Franck Perez (ORCID: https://orcid.org/0000-0002-9129-9401)
- Alessandra Murabito (ORCID: https://orcid.org/0000-0003-3039-4285)
- Mariadomenica Lupi (ORCID: https://orcid.org/0009-0007-7561-3572)
- Fabio Bedin (ORCID: https://orcid.org/0009-0006-4313-7762)
- Amir Fardin (ORCID: https://orcid.org/0000-0002-9472-408X)
- L. Andreoli
- Simona Fontana (ORCID: https://orcid.org/0000-0003-4681-2170)
- Sara Sigismund (ORCID: https://orcid.org/0000-0002-1396-4453)
- Federico Bussolino (ORCID: https://orcid.org/0000-0002-5348-1341)
- Rosa Pennisi (ORCID: https://orcid.org/0000-0001-6542-7898)
- Flavia Martino (ORCID: https://orcid.org/0009-0001-0224-7563)
- Gaelle Boncompain
- Bronislava Matoskova
Institutions
- Université Claude Bernard Lyon 1 (FR)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- University of Milan (IT)
- Université Paris Sciences et Lettres (FR)
- Sorbonne Université (FR)
- Institut NeuroMyoGène (FR)
- Torino e-district (IT)
- Department of Medical Sciences (BY)
- The San Raffaele Telethon Institute for Gene Therapy (IT)
- Candiolo Cancer Institute (IT)
- Biologie cellulaire et Cancer (FR)
- University of Turin (IT)
- European Institute of Oncology (IT)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-08-29
- DOI
- https://doi.org/10.1002/advs.202502269
- Citations
- 1
- Primary Topic
- Cellular transport and secretion
- Type
- article
- Field-Weighted Citation Impact
- 1.15
Funders
- Ministero della Salute
- Associazione Italiana per la Ricerca sul Cancro
- H2020 European Research Council