The orthologous human and murine semaphorin 6A-1 proteins (SEMA6A-1/Sema6A-1) bind to the enabled/vasodilator-stimulated phosphoprotein-like protein (EVL) via a novel carboxyl-terminal zyxin-like domain

Neuronal development and apoptosis critically depend on the transformation of extracellular signals to intracellular actions resulting in cytoskeletal rearrangements. Ena/VASP (enabled/vasodilator-stimulated phosphoprotein) p roteins play an important role in actin and filament dynamics, whereas memb ers of the semaphorin protein family are guidance signals in embryo- and or ganogenesis. Here, we report the identification of two novel transmembranou s human and murine semaphorins, (HSA)SEMA6A-1 and (MMU)Sema6A-1. These sema phorin 6 variants directly link the Ena/VASP and the semaphorin protein fam ily, since SEMA6A-1/Sema6A-1 is capable of a selective binding to the prote in EVL (Ena/VASP-like protein). EVL is the third member of the Ena/VASP fam ily of proteins that was identified sharing the same structural features as Mena (mammalian enabled) and VASP, although its functionality seems to be different from that of the other members. Here we demonstrate that SEMA6A-1 /Sema6A-1 is colocalized with EVL via its zyxin-like carboxyl-terminal doma in that contains a modified binding motif, which further stresses the exist ence of functional differences between EVL and Mena/VASP, In addition these findings suggest a completely new role for transmembranous semaphorins suc h as SEMA6A-1/Sema6A-1 in retrograde signaling.