Mechanical control of the alternative splicing factor PTBP1 regulates extracellular matrix stiffness induced proliferation and cell spreading
Pei-Li Tseng,
Weiwei Sun,
Ahmed Salem,
Mubarak Alaklobie,
Sarah C. Macfarlane,
Annica K.B. Gad,
Mark O. Collins,
Kai S. Erdmann
Affiliations
Pei-Li Tseng
School of Biosciences, University of Sheffield, Sheffield S10 2TN, UK
Weiwei Sun
School of Biosciences, University of Sheffield, Sheffield S10 2TN, UK
Ahmed Salem
School of Biosciences, University of Sheffield, Sheffield S10 2TN, UK; Department of Biomedical Laboratory Science, Sheba University, Sheba, Libya
Mubarak Alaklobie
School of Biosciences, University of Sheffield, Sheffield S10 2TN, UK; Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, Bisha 67714, Saudi Arabia
Sarah C. Macfarlane
Department of Oncology and Metabolism, The Medical School, University of Sheffield, Sheffield S10 2TN, UK
Annica K.B. Gad
Department of Oncology and Metabolism, The Medical School, University of Sheffield, Sheffield S10 2TN, UK; Department of Oncology-Pathology, Karolinska Institutet, Anna Steckséns gata 30A, 171 64 Solna, Sweden; CQM - Centro de Química da Madeira, Universidade da Madeira, Campus da Penteada, 9020-105 Funchal, Portugal
Mark O. Collins
School of Biosciences, University of Sheffield, Sheffield S10 2TN, UK; biOMICS Mass Spectrometry Facility, University of Sheffield, Sheffield S10 2TN, UK
Kai S. Erdmann
School of Biosciences, University of Sheffield, Sheffield S10 2TN, UK; Corresponding author
Summary: Cells sense mechanical cues and convert them into biochemical responses to regulate biological processes such as embryonic development, aging, cellular homeostasis, and disease progression. In this study, we introduce a large-scale, systematic approach to identify proteins with mechanosensitive nuclear localization, highlighting their potential roles in mechanotransduction. Among the proteins identified, we focus here on the splicing factor PTBP1. We demonstrate that its nuclear abundance is regulated by mechanical cues such as cell density, size, and extracellular matrix (ECM) stiffness and that PTBP1 medicates the mechanosensitive alternative splicing of the endocytic adapter protein Numb. Furthermore, we show that PTBP1 and Numb alternative splicing is critical for ECM stiffness–induced epithelial cell spreading and proliferation as well as for mesenchymal stem cell differentiation into osteoblasts on a stiff matrix. Our results underscore the emerging role of alternative splicing in mechanotransduction and provide novel mechanistic insights into how matrix stiffness modulates cellular mechanoresponses.
