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00085472can071906-sup-suppl_fig_4.pdf (30.43 kB)

Supplementary Figure 4 from Novel Noncatalytic Role for Caspase-8 in Promoting Src-Mediated Adhesion and Erk Signaling in Neuroblastoma Cells

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posted on 2023-03-30, 17:44 authored by Darren Finlay, Kristiina Vuori
Supplementary Figure 4 from Novel Noncatalytic Role for Caspase-8 in Promoting Src-Mediated Adhesion and Erk Signaling in Neuroblastoma Cells

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ARTICLE ABSTRACT

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. [Cancer Res 2007;67(24):11704–11]

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