Novel noncatalytic role for caspase-8 in promoting SRC-mediated adhesion and Erk signaling in neuroblastoma cells.
Neuroblastomas are extremely aggressive, although heterogeneous, cancers with a poor prognosis upon metastasis. Some evidence has suggested a correlative silencing of caspase-8 with MYCN amplification in neuroblastoma. A prognostic effect of this silencing, however, has been disputed. We report here hitherto undescribed roles for caspase-8 in the modulation of cell adhesion and subsequent activation of the Erk signaling pathway. Re-expression of caspase-8 in neuroblastoma cells lacking endogenous caspase-8 expression was found to promote cell adhesion to extracellular matrix and to activate adhesion-dependent signaling pathways, such as the Erk kinase cascade. This function of caspase-8 occurred irrespective of its proteolytic activity. Additionally, a pool of caspase-8 was shown to co-localize with the Src tyrosine kinase at the cellular periphery. Furthermore, our studies showed that caspase-8 forms a physical protein complex with Src via its death effector domains (DED) and maintains the complex in a detergent-soluble fraction. We also show that the DEDs of caspase-8 alone are necessary and sufficient to recreate the adhesive and biochemical phenotypes observed with the full-length protein, suggesting that caspase-8 may exert these effects via its association with Src. This protein complex association of caspase-8 and Src, and concomitant downstream signaling events, may help reconcile why a potential tumor suppressor such as caspase-8 is rarely absent in cancers.
Finlay
Darren
D
Cancer Center, Burnham Institute for Medical Research, La Jolla, California 92037, USA.
Vuori
Kristiina
K
D056769:Alstrom Syndrome; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D016147:Genes, Tumor Suppressor; D006801:Humans; D007668:Kidney; D009447:Neuroblastoma; D012334:RNA, Neoplasm / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D019061:src-Family Kinases / Q000502:physiology*
D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D019061:src-Family Kinases; D053181:Caspase 8