PUBLICATION
SH3BP5L triggers the RAB11A-regulated integrin recycling network implicated in breast cancer metastasis
- Authors
- Li, H., De Santis, M.C., Tucci, F.A., Tosoni, D., Zhang, P., Jenkins, M.L., Villari, G., Filippone, M.G., Guerrera, E., Tealdi, S., Gozzelino, L., Gulluni, F., Prever, L., Zanini, C., Forni, M., Franco, I., Martini, M., Burke, J.E., Serini, G., Campa, C.C., Pece, S., Margaria, J.P., Hirsch, E.
- ID
- ZDB-PUB-260203-7
- Date
- 2026
- Source
- The Journal of Clinical Investigation 136: (Journal)
- Registered Authors
- Keywords
- Breast cancer, Cell biology, Cell migration/adhesion, Oncology, Protein traffic
- MeSH Terms
-
- Adaptor Proteins, Signal Transducing*/genetics
- Adaptor Proteins, Signal Transducing*/metabolism
- Animals
- Breast Neoplasms*/genetics
- Breast Neoplasms*/metabolism
- Breast Neoplasms*/pathology
- Cell Line, Tumor
- Female
- Guanine Nucleotide Exchange Factors*/genetics
- Guanine Nucleotide Exchange Factors*/metabolism
- Humans
- Integrin beta1*/genetics
- Integrin beta1*/metabolism
- Kinesins/genetics
- Kinesins/metabolism
- Lung Neoplasms*/genetics
- Lung Neoplasms*/metabolism
- Lung Neoplasms*/secondary
- Mice
- Neoplasm Metastasis
- Neoplasm Proteins*/genetics
- Neoplasm Proteins*/metabolism
- Triple Negative Breast Neoplasms*/genetics
- Triple Negative Breast Neoplasms*/metabolism
- Triple Negative Breast Neoplasms*/pathology
- Zebrafish
- rab GTP-Binding Proteins*/genetics
- rab GTP-Binding Proteins*/metabolism
- PubMed
- 41623179 Full text @ Journal of Clin. Invest.
Citation
Li, H., De Santis, M.C., Tucci, F.A., Tosoni, D., Zhang, P., Jenkins, M.L., Villari, G., Filippone, M.G., Guerrera, E., Tealdi, S., Gozzelino, L., Gulluni, F., Prever, L., Zanini, C., Forni, M., Franco, I., Martini, M., Burke, J.E., Serini, G., Campa, C.C., Pece, S., Margaria, J.P., Hirsch, E. (2026) SH3BP5L triggers the RAB11A-regulated integrin recycling network implicated in breast cancer metastasis. The Journal of Clinical Investigation. 136:.
Abstract
Metastatic progression in aggressive breast cancer (BC) depends on a tightly controlled vesicular recycling network regulated by RAB11, a small guanosine triphosphate enzyme (GTPase). In a cohort of more than 1,000 patients with BC, we identified SH3BP5L as the most highly expressed guanine nucleotide exchange factor (GEF) for RAB11A. High SH3BP5L expression marked an advanced tumor stage, distant metastasis, and poor prognosis, with significant associations in human epidermal growth factor receptor 2-positive (HER2+) and triple-negative breast cancer (TNBC). Using Förster resonance energy transfer (FRET) sensors and artificial intelligence- (AI-assisted) microscopy, we showed that cargo delivery to the plasma membrane required SH3BP5L-dependent activation of RAB11A and assembly of a complex with the anterograde motor KIF5B. This trafficking governed key metastatic features of TNBC, including β1 integrin recycling and α3β1 integrin surface exposure. Inhibition of SH3BP5L or its GEF activity reduced cell spreading in zebrafish and lung metastasis in mouse models, revealing a previously unidentified driver of BC dissemination and a potential therapeutic vulnerability.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping