title: The focal adhesion-localized CdGAP regulates matrix rigidity sensing and durotaxis.
abstract: Motile cells are capable of sensing the stiffness of the surrounding extracellular matrix through integrin-mediated focal adhesions and migrate towards regions of higher rigidity in a process known as durotaxis. Durotaxis plays an important role in normal development and disease progression, including tumor invasion and metastasis. However, the signaling mechanisms underlying focal adhesion-mediated rigidity sensing and durotaxis are poorly understood. Utilizing matrix-coated polydimethylsiloxane gels to manipulate substrate compliance, we show that cdGAP, an adhesion-localized Rac1 and Cdc42 specific GTPase activating protein, is necessary for U2OS osteosarcoma cells to coordinate cell shape changes and migration as a function of extracellular matrix stiffness. CdGAP regulated rigidity-dependent motility by controlling membrane protrusion and adhesion dynamics, as well as by modulating Rac1 activity. CdGAP was also found to be necessary for U2OS cell durotaxis. Taken together, these data identify cdGAP as an important component of an integrin-mediated signaling pathway that senses and responds to mechanical cues in the extracellular matrix in order to coordinate directed cell motility.
authors.affiliation: Department of Cell and Developmental Biology, State University of New York Upstate Medical University, Syracuse, New York, United States of America.
authors.forename: Duncan B
authors.initials: DB
authors.lastname: Wormer
authors.affiliation: Syracuse Biomaterials Institute, Syracuse University, Syracuse, New York, United States of America.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Davis
authors.affiliation: Syracuse Biomaterials Institute, Syracuse University, Syracuse, New York, United States of America.
authors.forename: James H
authors.initials: JH
authors.lastname: Henderson
authors.affiliation: Department of Cell and Developmental Biology, State University of New York Upstate Medical University, Syracuse, New York, United States of America.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Turner
mesh_terms: D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics; D005109:Extracellular Matrix / Q000378:metabolism*; D022001:Focal Adhesions / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: C514543:ARHGAP31 protein, human; D020690:GTPase-Activating Proteins; D010750:Phosphoproteins; D020830:rac1 GTP-Binding Protein