title: A FAK-Cas-Rac-lamellipodin signaling module transduces extracellular matrix stiffness into mechanosensitive cell cycling.
abstract: Tissue and extracellular matrix (ECM) stiffness is transduced into intracellular stiffness, signaling, and changes in cellular behavior. Integrins and several of their associated focal adhesion proteins have been implicated in sensing ECM stiffness. We investigated how an initial sensing event is translated into intracellular stiffness and a biologically interpretable signal. We found that a pathway consisting of focal adhesion kinase (FAK), the adaptor protein p130Cas (Cas), and the guanosine triphosphatase Rac selectively transduced ECM stiffness into stable intracellular stiffness, increased the abundance of the cell cycle protein cyclin D1, and promoted S-phase entry. Rac-dependent intracellular stiffening involved its binding partner lamellipodin, a protein that transmits Rac signals to the cytoskeleton during cell migration. Our findings establish that mechanotransduction by a FAK-Cas-Rac-lamellipodin signaling module converts the external information encoded by ECM stiffness into stable intracellular stiffness and mechanosensitive cell cycling. Thus, lamellipodin is important not only in controlling cellular migration but also for regulating the cell cycle in response to mechanical signals.
authors.affiliation: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. yob@mail.med.upenn.edu assoian@mail.med.upenn.edu.
authors.forename: Yong Ho
authors.initials: YH
authors.lastname: Bae
authors.affiliation: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Keeley L
authors.initials: KL
authors.lastname: Mui
authors.affiliation: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Bernadette Y
authors.initials: BY
authors.lastname: Hsu
authors.affiliation: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Shu-Lin
authors.initials: SL
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Cretu
authors.affiliation: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Ziba
authors.initials: Z
authors.lastname: Razinia
authors.affiliation: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Tina
authors.initials: T
authors.lastname: Xu
authors.affiliation: Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Puré
authors.affiliation: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. yob@mail.med.upenn.edu assoian@mail.med.upenn.edu.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Assoian
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002453:Cell Cycle; D050719:Crk-Associated Substrate Protein / Q000378:metabolism*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D040542:Mechanotransduction, Cellular; D051379:Mice; D015398:Signal Transduction
chemical_list: D002352:Carrier Proteins; D050719:Crk-Associated Substrate Protein; D051416:Focal Adhesion Protein-Tyrosine Kinases