The intracellular domain of the human transmembrane protocadheriun Fat1 is involved in actin cytoskeleton regulation by the interaction of its class I EVH1 binding domain with Ena/Vasp (Tanoue & Takeichi, J. Cell Sci. 118 (2005) 2347). We have identified the scaffolding proteins Homer-3 (and Homer-1) to interact with an overlapping class II EVH1 binding domain by pull-down experiments, mass spectrometry, and subsequent binding and mutation analyses. Homer proteins are known to form complexes with several actors at critical key points of signalling pathways, such as the metabotropic glutamate receptors, IP3-dependent Ca2+ and transient receptor potential ion channels, small GTPases, cytoskeletal proteins, and transcription factors. Binding of hFat1 to Homer proteins is selective and competes with mammalian Ena. Like the intracellular domain of hFat1, Homer-3 is translocated to the nucleus and affects serum response element -dependent transcription. Homer proteins are linked to cocaine-induced neurological effects and may be involved in the pathogenesis of schizophrenic disorders. Remarkably, the genomic locus encoding the intracellular domain of hFat1 has been recently identified to confer susceptibility to familial bipolar disorder in four independent cohorts (Blair et al. 2006).