Background: Eph receptors play important functions in developmental processes
and diseases and among them EphA2 is well known for its controversial role in cancer.
Drug discovery strategies are mainly centered on EphA2 extracellular ligand-binding domain
however, the receptor also contains a largely unexplored cytosolic Sam (Sterile alpha
motif) domain at the C-terminus. EphA2-Sam binds the Sam domain from the lipid phosphatase
Ship2 and the first Sam domain of Odin. Sam-Sam interactions may be important to
regulate ligand-induced receptor endocytosis and degradation i.e., processes that could be
engaged against tumor malignancy.
Methods: We critically analyzed literature related to a) Eph receptors with particular emphasis
on EphA2 and its role in cancer, b) Sam domains, c) heterotypic Sam-Sam interactions
Results: While literature data indicate that binding of EphA2-Sam to Ship2-Sam should
largely generate pro-oncogenic effects in cancer cells, the correlation between EphA2-
Sam/Odin-Sam1 complex and the disease is unclear. Recently a few linear peptides encompassing
binding interfaces from either Ship2-Sam and Odin-Sam1 have been characterized
but failed to efficiently block heterotypic Sam-Sam interactions involving EphA2-Sam due
to the lack of a native like fold.
Conclusion: Molecule antagonists of heterotypic EphA2-Sam associations could work as
potential anticancer agents or be implemented as tools to further clarify receptor functions
and eventually validate its role as a novel target in the field of anti-cancer drug discovery.
Due to the failure of linear peptides there is a crucial need for novel approaches, based on
cyclic or helical molecules, to target Sam-Sam interfaces.