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

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.