Association of frabin with the actin cytoskeleton is essential for microspike formation through activation of Cdc42 small G protein.

We have recently isolated a novel actin filament-binding protein, named frabin. Frabin has one actin filament-binding domain (ABD), one Dbl homology domain (DHD), first pleckstrin homology domains (PHD) adjacent to DHD, one cysteine rich-domain (CRD), and second PHD from the N terminus to the C terminus in this order. Full-length frabin induces microspike formation and c-Jun N-terminal kinase (JNK) activation. We found here that the fragment of frabin containing DHD and first PHD stimulated guanine nucleotide exchange of Cdc42Hs small G protein, but not that of RhoA or Rac1 small G protein. However, this fragment of frabin did not induce microspike formation, and ABD was additionally necessary for microspike formation. Frabin having ABD was associated with the actin cytoskeleton, whereas frabin lacking ABD was diffusely distributed in the cytoplasm. In contrast, ABD was not necessary for JNK activation but CRD and second PHD were additionally necessary for this activation. These results indicate that the association of frabin with the actin cytoskeleton is essential for microspike formation but not for JNK activation and that different domains of frabin are involved in microspike formation and JNK activation through Cdc42 activation.