Molecular dissection of NRG1-ERBB4 signaling implicates PTPRZ1 as a potential schizophrenia susceptibility gene

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 b/f (RPTPb), we postulated that simultaneous binding of MAGI proteins to RPTPb and ERBB4 forms a phosphotyrosine kinase/phosphotyrosine phosphatase complex. Studies in cultured cells confirmed both a spatial and functional association between ERBB4, MAGI and RPTPb. Given the evidence for this functional association, we examined the genes coding for MAGI and RPTPb for genetic association with schizophrenia in a Caucasian United Kingdom case-control cohort (n = B1400). PTPRZ1, which codes for RPTPb, 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; hypothesiswide P = 0.026). The data provide evidence for a role of PTPRZ1, and for RPTPb signaling abnormalities, in the etiology of schizophrenia. Furthermore, the data indicate a role for RPTPb 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.

No association between the protein tyrosine phosphatase, receptor‐type, Z Polypeptide 1 (PTPRZ1) gene and schizophrenia in the Japanese population

“…In this study, we could not replicate a previous report [Buxbaum et al, 2007], which revealed a significant association between PTPRZ1 and schizophrenia in a Caucasian population. The discrepancy between Japanese and Caucasian populations may derive from ethnic differences in the etiology of schizophrenia.…”

“…Then we defined 28 tagging SNPs (Table I) with the criterion of an r 2 > 0.8 in 'pair-wise tagging only' mode using the 'Tagger' program, implemented by Haploview software version 4.0 (http://www.broad.mit.edu/mpg/haploview/index.php) [Barrett et al, 2005;de Bakker et al, 2005], considering two points in particular. First, we mandatorily included marginal and significant SNPs reported in previous study (Table I; rs6466808, rs10278079, rs1196471, rs2693657, rs1147502, rs1147497, rs1147489, and rs1206381; indicated by asterisk) as tagging SNPs, except for rs1196513 and rs13241278 [Buxbaum et al, 2007]. Because rs1196513 and rs13241278…”

“…Likewise, MAGI proteins are dephosphorylated by receptor protein tyrosine phosphatase beta (RPTPb) [Fukada et al, 2005], and thus notably, RPTPb may also regulate the NRG1-ERBB4 signaling [Buxbaum et al, 2007].…”

“…In the aforementioned NRG1-ERBB4 study, a case-control association study between PTPRZ1 and schizophrenia has been carried out, and PTPRZ1 has been demonstrated to be associated with schizophrenia in a United Kingdom casecontrol cohort [Buxbaum et al, 2007]. However, while PTPRZ1 is considered to be one of the plausible candidate genes for schizophrenia, replication of this positive association is required in order to demonstrate that PTPRZ1 is a true susceptibility gene for this disease.…”

Receptor-type Protein-tyrosine Phosphatase ζ Is a Functional Receptor for Interleukin-34

“…Furthermore, the soluble PTP-isoform has been shown to be necessary for maturation of oligodendrocyte progenitors to differentiated myelin-secreting oligodendrocytes in vitro (77), and PTP--deficient mice exhibit increased myelin breakdown (78). In addition, the PTPRZ1 gene in humans is a schizophreniasusceptibility gene (79), and PTP-regulates tyrosine phosphorylation of voltage-gated sodium channels in neurons (80). Given the multiplicity of ligands for PTP-, the role of IL-34 regulation in these settings will need to be further defined.…”