Mechanical Cues Regulate Cargo Sorting and Export at the Golgi
The secretory pathway is a sophisticated endomembrane machinery designed to transport and deliver proteins and lipids to intracellular organelles and the extracellular space. While the molecular components of the secretory pathway are well understood, less is known about their regulation, especially by mechanical cues. Here, it is reported that substrate stiffness stimulates conventional secretion. A molecular pathway is unravelled that links a mechanical cue through proto-oncogene tyrosine-protein kinase Src (Src) and focal adesion kinase (FAK) kinases to promote the trafficking of secretory proteins out of the Golgi apparatus and prevent their post-Golgi lysosomal degradation. Phosphoproteomic analysis revealed the Golgi-specific Brefeldin A resistance factor 1 (GBF1) as a key downstream mechano-responsive regulator, whose phosphorylation state orchestrates post-Golgi cargo sorting, directing proteins either toward secretion or to lysosomes. Finally, AMP-activated protein kinase (AMPK) is identified as a stiffness-dependent upstream regulator of GBF1 phosphorylation. Together, the data reveal a molecular regulatory loop in which matrix stiffness positively regulates cellular secretion via the Src-FAK-AMPK-GBF1 axis, which can have relevant medical implications in conditions like cancer and fibrosis and their treatment.
Authors
- Stefania Forciniti (ORCID: https://orcid.org/0000-0001-6719-1591)
- Marinella Pirozzi (ORCID: https://orcid.org/0000-0002-1714-2000)
- Riccardo Rizzo (ORCID: https://orcid.org/0000-0002-5716-9195)
- Domenico Russo (ORCID: https://orcid.org/0000-0003-2171-657X)
- Seetharaman Parashuraman (ORCID: https://orcid.org/0000-0001-5113-4592)
- Giuseppe Gigli (ORCID: https://orcid.org/0000-0002-2583-5747)
- Giovanni D’Angelo (ORCID: https://orcid.org/0000-0002-0734-4127)
- Antonio Galeone (ORCID: https://orcid.org/0000-0002-8678-7726)
- Elizabeth Sztul (ORCID: https://orcid.org/0000-0002-9091-875X)
- Tiziano Verri (ORCID: https://orcid.org/0000-0003-4983-2767)
- Rossella Venditti (ORCID: https://orcid.org/0000-0002-1884-6501)
- Loris Rizzello (ORCID: https://orcid.org/0000-0002-8230-853X)
- Edoardo Scarpa (ORCID: https://orcid.org/0000-0002-5886-6929)
- Gabriella De Blasi
- Lucia Santorelli (ORCID: https://orcid.org/0000-0002-1883-712X)
- Paolo Grumati (ORCID: https://orcid.org/0000-0002-9942-9389)
- Eunjoo H. Lee (ORCID: https://orcid.org/0000-0002-5569-0067)
- Sara Costantini (ORCID: https://orcid.org/0000-0002-6977-9601)
- Alessia Calcagnì (ORCID: https://orcid.org/0000-0002-1946-5815)
- Loretta L. del Mercato (ORCID: https://orcid.org/0000-0001-9733-7088)
- Antonio Ranieri
- Greta Serafino
Institutions
- University of Salento (IT)
- University of Milan (IT)
- University of Alabama at Birmingham (US)
- Istituto di Nanotecnologia (IT)
- Institute of Molecular Genetics (RU)
- Institute for Experimental Endocrinology and Oncology (IT)
- Mylan (Switzerland) (CH)
- Telethon Institute Of Genetics And Medicine (IT)
- Istituto Nazionale Genetica Molecolare (IT)
- École Polytechnique Fédérale de Lausanne (CH)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-10-14
- DOI
- https://doi.org/10.1002/advs.202506241
- Citations
- 1
- Primary Topic
- Cellular transport and secretion
- Type
- article
- Field-Weighted Citation Impact
- 1.15