1. ¹Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA
2. ²Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA
3. ³Department of Human Genetics, Mount Sinai School of Medicine, New York, NY, USA
4. ⁴Department of Psychological Medicine, School of Medicine, Cardiff University, Heath Park, Cardiff, UK
5. ⁵Neurobiology Program, Department of Neurology, Children's Hospital, Harvard Medical School, Boston, MA, USA
6. ⁶Institut Pasteur, Département De Neuroscience, Paris, France
7. ⁷Department of Pharmacology, Mount Sinai School of Medicine, New York, NY, USA

Correspondence: Dr JD Buxbaum, Department of Psychiatry, Mount Sinai School of Medicine, One Gustave L Levy Place, Box 1668, New York, NY 10029, USA. E-mail: joseph.buxbaum@mssm.edu

Received 14 November 2006; Revised 4 February 2007; Accepted 6 February 2007; Published online 17 April 2007.

Abstract

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 / (RPTP), we postulated that simultaneous binding of MAGI proteins to RPTP and ERBB4 forms a phosphotyrosine kinase/phosphotyrosine phosphatase complex. Studies in cultured cells confirmed both a spatial and functional association between ERBB4, MAGI and RPTP. Given the evidence for this functional association, we examined the genes coding for MAGI and RPTP for genetic association with schizophrenia in a Caucasian United Kingdom case–control cohort (n=1400). PTPRZ1, which codes for RPTP, 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 RPTP signaling abnormalities, in the etiology of schizophrenia. Furthermore, the data indicate a role for RPTP 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.