Neuregulin and the
neuregulin receptor ERBB4 have been genetically and functionally implicated in
schizophrenia. In this study, we used the yeast two-hybrid system to identify
proteins that interact with ERBB4, to identify genes and pathways that might contribute to
schizophrenia susceptibility. We identified the MAGI scaffolding
proteins as ERBB4-binding
proteins. After validating the interaction of MAGI
proteins with ERBB4 in mammalian cells, we demonstrated that ERBB4 expression, alone or in combination with ERBB2 or ERBB3, led to the
tyrosine phosphorylation of MAGI
proteins, and that this could be further enhanced with receptor activation by
neuregulin. As MAGI
proteins were previously shown to interact with receptor
phosphotyrosine phosphatase beta/zeta (
RPTPbeta), we postulated that simultaneous binding of MAGI
proteins to
RPTPbeta and ERBB4 forms a
phosphotyrosine kinase/
phosphotyrosine phosphatase complex. Studies in cultured cells confirmed both a spatial and functional association between ERBB4, MAGI and
RPTPbeta. Given the evidence for this functional association, we examined the genes coding for MAGI and
RPTPbeta for genetic association with
schizophrenia in a Caucasian United Kingdom case-control cohort (n= approximately 1400). PTPRZ1, which codes for
RPTPbeta, showed significant, gene-wide and hypothesis-wide association with
schizophrenia in our study (best individual single-nucleotide polymorphism allelic P=0.0003; gene-wide P=0.0064; hypothesis-wide P=0.026). The data provide evidence for a role of PTPRZ1, and for
RPTPbeta signaling abnormalities, in the etiology of
schizophrenia. Furthermore, the data indicate a role for
RPTPbeta in the modulation of ERBB4 signaling that may in turn provide further support for an important role of
neuregulin/ERBB4 signaling in the molecular basis of
schizophrenia.