title: Caspase-8 association with the focal adhesion complex promotes tumor cell migration and metastasis.
abstract: Caspase-8 is a proapoptotic protease that suppresses neuroblastoma metastasis by inducing programmed cell death. Paradoxically, caspase-8 can also promote cell migration among nonapoptotic cells; here, we show that caspase-8 can promote metastasis when apoptosis is compromised. Migration is enhanced by caspase-8 recruitment to the cellular migration machinery following integrin ligation. Caspase-8 catalytic activity is not required for caspase-8-enhanced cell migration; rather, caspase-8 interacts with a multiprotein complex that can include focal adhesion kinase and calpain 2 (CPN2), enhancing cleavage of focal adhesion substrates and cell migration. Caspase-8 association with CPN2/calpastatin disrupts calpastatin-mediated inhibition of CPN2. In vivo, knockdown of either caspase-8 or CPN2 disrupts metastasis among apoptosis-resistant tumors. This unexpected molecular collaboration provides an explanation for the continued or elevated expression of caspase-8 observed in many tumors.
authors.affiliation: Department of Pathology, Moores UCSD Cancer Center, University of California-San Diego, San Diego, California 92093, USA.
authors.forename: Simone
authors.initials: S
authors.lastname: Barbero
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Mielgo
authors.forename: Vicente
authors.initials: V
authors.lastname: Torres
authors.forename: Tal
authors.initials: T
authors.lastname: Teitz
authors.forename: David J
authors.initials: DJ
authors.lastname: Shields
authors.forename: David
authors.initials: D
authors.lastname: Mikolon
authors.forename: Matthew
authors.initials: M
authors.lastname: Bogyo
authors.forename: Daniela
authors.initials: D
authors.lastname: Barilà
authors.forename: Jill M
authors.initials: JM
authors.lastname: Lahti
authors.forename: David
authors.initials: D
authors.lastname: Schlaepfer
authors.forename: Dwayne G
authors.initials: DG
authors.lastname: Stupack
mesh_terms: D056769:Alstrom Syndrome; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D022001:Focal Adhesions / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D009447:Neuroblastoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D016608:Talin / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D016608:Talin; C033668:calpastatin; D051416:Focal Adhesion Protein-Tyrosine Kinases; C505530:CASP8 protein, human; D002154:Calpain; D053181:Caspase 8; C569870:CAPN2 protein, human