title: Src-inducible association of CrkL with procaspase-8 promotes cell migration.
abstract: Procaspase-8, the zymogen form of the apoptosis-initiator caspase-8, undergoes phosphorylation following integrin-mediated cell attachment to an extracellular matrix substrate. Concordant with cell attachment to fibronectin, a population of procaspase-8 becomes associated with a peripheral insoluble compartment that includes focal complexes and lamellar microfilaments. Phosphorylation of procaspase-8 both impairs its maturation to the proapoptotic form and can promote cell migration. Here we show that the cytoskeletal adaptor protein CrkL promotes caspase-8 recruitment to the peripheral spreading edge of cells, and that the catalytic domain of caspase-8 directly interacts with the SH2 domain of CrkL. We show that the interaction is abolished by shRNA-mediated silencing of Src, in Src-deficient MEFs, and by pharmacologic inhibitors of the kinase. The results provide insight into how tyrosine kinases may act to coordinate the suppression caspase-8 mediated apoptosis, while promoting cell invasion.
authors.affiliation: Department of Reproductive Medicine; Division of Gynecologic Oncology; University of California San Diego School of Medicine; La Jolla, CA USA; The UCSD Moores Cancer Center; La Jolla, CA USA; Graduate School of Biomedical Sciences, Sanford-Burnham Medical Research Institute, La Jolla, CA USA.
authors.forename: Ryon
authors.initials: R
authors.lastname: Graf
authors.forename: Simone
authors.initials: S
authors.lastname: Barbero
authors.forename: Nadine
authors.initials: N
authors.lastname: Keller
authors.forename: Lauren
authors.initials: L
authors.lastname: Chen
authors.forename: Sean
authors.initials: S
authors.lastname: Uryu
authors.forename: David
authors.initials: D
authors.lastname: Schlaepfer
authors.forename: Dwayne
authors.initials: D
authors.lastname: Stupack
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; D009687:Nuclear Proteins; D019061:src-Family Kinases; D053181:Caspase 8
keywords: Crk; Crk-L; FAK; Src; caspase 8; phosphorylation