DataVXAdvanced SciencePaper
journal article·2025-11Open access

Polycystin‐1 Mutant Alters Mechanotransduction in Response to Collagen and Extracellular Matrix Stiffness via Daam1‐Dependent Microfilament Remodeling

Jiaofeng Zhou, Yibing Deng, Jie Mei, Mengyun Wan, Ningyi Xue, Xinyu Zong, Ji Zhou, Junli Ding, Ting Yan, Yu Jiang, Tiansong Xia, Peng Zheng, Yichao Zhu

Advanced Science· Volume 12· Issue 41
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Abstract

Abstract Extracellular matrix (ECM) stiffness‐mediated mechanotransduction is a common signaling scheme in both physiological and pathological contexts; however, its molecular mechanisms remain incompletely understood. Polycystin‐1 is a transmembrane protein that is known to participate in mechano‐transduction. Here, it is demonstrated that, in response to extracellular collagen and increased ECM stiffness, polycystin‐1 interacts with disheveled‐associated activator of morphogenesis 1 (Daam1), a cytoskeletal regulator, thereby promoting microfilament remodeling, cellular protrusion formation, and enhanced motility of tumor cells through activating the RhoA signaling axis. Wild‐type polycystin‐1 is susceptible to proteolytic cleavage at the G protein‐coupled receptor proteolysis site. Using atomic force microscopy‐based single‐molecule force spectroscopy, direct evidence is provided that polycystin‐1 variants R3039H and L3048H exhibit reduced cleavage susceptibility in vitro. Notably, R3039H is associated with lymphatic and distant metastasis in breast cancer and augments mechanotransduction by facilitating the nuclear translocation of Yes‐associated protein and upregulating the expression of connective tissue growth factor and collagen in tumor cells and cancer‐associated fibroblasts, respectively. Collectively, our findings identify polycystin‐1 as a mechanosensor of collagen and ECM stiffness that modulates tumor cell migration via the Daam1/RhoA/YAP signaling cascade.
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Research context

OpenAlex topics: Genetic and Kidney Cyst Diseases · Microtubule and mitosis dynamics · Biomedical Research and Pathophysiology

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Physiology School of Basic Medical Sciences Nanjing Medical University Nanjing Jiangsu 211166 China

State Key Laboratory of Coordination Chemistry School of Chemistry and Chemical Engineering Chemistry and Biomedicine Innovation Centre (ChemBIC) Nanjing University Nanjing Jiangsu 210023 China

The First Clinical Medicine College Nanjing Medical University Nanjing Jiangsu 211166 China

Department of Breast Surgery The First Affiliated Hospital of Nanjing Medical University Nanjing Jiangsu 210029 China

Pancreas Center The First Affiliated Hospital of Nanjing Medical University Nanjing Jiangsu 210029 China

Department of Oncology The Affiliated Wuxi People's Hospital of Nanjing Medical University Wuxi Medical Center Nanjing Medical University Wuxi Jiangsu 214023 China

Safety Assessment and Research Center for Drug Pesticide and Veterinary Drug of Jiangsu Province Nanjing Medical University Nanjing Jiangsu 211166 China

Department of Pharmacology and Chemical Biology University of Pittsburgh School of Medicine Pittsburgh Pennsylvania 15261 USA

Department of General Surgery The Affiliated Taizhou People's Hospital of Nanjing Medical University Taizhou School of Clinical Medicine Nanjing Medical University Taizhou Jiangsu 225300 China

Funding

National Natural Science Foundation of China

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