SH3BP5L triggers the RAB11A-regulated integrin recycling network implicated in breast cancer metastasis.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41623179.
- Also identified by DOI 10.1172/JCI192705 and PMC identifier 12867135.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- rab GTP-Binding Proteins
- Triple Negative Breast Neoplasms
- Integrin beta1
- Lung Neoplasms
- Adaptor Proteins, Signal Transducing
- Guanine Nucleotide Exchange Factors
- Breast Neoplasms
- Neoplasm Proteins