UC San Diego

Caspase-8 is a cytosolic cysteine protease that induces programmed cell death by processing a variety of apoptotic substrates [1]. Conversely, it has been shown to have non- apoptotic functions and is upregulated in many cancers, including ovarian cancer [2, 3]. In neuroblastoma cells, post-translational modification of caspase-8 by tyrosine phosphorylation has been shown to promote cell adhesion and migration, which are hallmarks of cancer cells [2, 4, 5]. Phosphorylated tyrosine residues may bind to SH2 (src homology 2) domains, which are present in 121 human proteins, and may be involved in caspase-8 dependent migration. The regulatory subunit of PI3K (phosphoinositide-3 kinase) p85[alpha] contains two SH2 domains, and has been previously suggested to be involved in migration [2]. Here, I characterize a direct and typical SH2-phosphotyrosine interaction between the Y380 of caspase-8 and the nSH2 domain of p85[alpha] in ovarian cancer cells. In addition, caspase-8 appears to promote adhesion in ovarian cancer cells, but potentially in a manner that is independent of the Y380 site. Protein modeling of caspase-8/p85p85[alpha]/p110[alpha] reveals potential mechanisms in which such an interaction could affect PI3K signaling. Understanding the implications of a caspase-8 and p85[alpha] interaction may further clarify the mechanisms by which caspase-8's dual roles are regulated, providing insight into the paradoxical retention of the caspase during tumor progression, as well as for therapies directed at optimizing tumor cell death.