Opposing actions of the synapse-associated protein of 97-kDa molecular weight (SAP97) and Disrupted in Schizophrenia 1 (DISC1) on Wnt/β-catenin signaling

M Boccitto; S Doshi; I P Newton; I Nathke; R Neve; F Dong; Y Mao; J Zhai; L Zhang; R Kalb

doi:10.1016/j.neuroscience.2016.03.048

Opposing actions of the synapse-associated protein of 97-kDa molecular weight (SAP97) and Disrupted in Schizophrenia 1 (DISC1) on Wnt/β-catenin signaling

Neuroscience. 2016 Jun 21:326:22-30. doi: 10.1016/j.neuroscience.2016.03.048. Epub 2016 Mar 26.

Authors

M Boccitto¹, S Doshi², I P Newton³, I Nathke³, R Neve⁴, F Dong⁵, Y Mao⁵, J Zhai⁶, L Zhang⁶, R Kalb⁷

Affiliations

¹ Department of Pediatrics, Division of Neurology, Research Institute, Children's Hospital of Philadelphia, Room 814, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA; Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: marco.boccitto@yale.edu.
² Department of Pediatrics, Division of Neurology, Research Institute, Children's Hospital of Philadelphia, Room 814, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA; Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
³ Cell & Developmental Biology, School of Life Sciences, University of Dundee, Dundee, DD15EH, UK.
⁴ Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research at the Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁵ Department of Biology, Penn State University, 214 Life Sciences Building, University Park, PA 16802, USA.
⁶ Department of Pediatrics, Division of Neurology, Research Institute, Children's Hospital of Philadelphia, Room 814, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA.
⁷ Department of Pediatrics, Division of Neurology, Research Institute, Children's Hospital of Philadelphia, Room 814, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA; Department of Neurology, Perelman School of Medicine University of Pennsylvania, Philadelphia, PA 19104, USA.

Abstract

It has been suggested that synapse-associated protein of 97-kDa molecular weight (SAP97) is a susceptibility factor for childhood and adult neuropsychiatric disorders. SAP97 is a scaffolding protein that shares direct and indirect binding partners with the Disrupted in Schizophrenia 1 (DISC1) gene product, a gene with strong association with neuropsychiatric disorders. Here we investigated the possibility that these two proteins converge upon a common molecular pathway. Since DISC1 modifies Wnt/β-catenin signaling via changes in glycogen synthase kinase 3 beta (GSK3β) phosphorylation, we asked if SAP97 impacts Wnt/β-catenin signaling and GSK3β phosphorylation. We find that SAP97 acts as inhibitor of Wnt signaling activity and can suppress the stimulatory effects of DISC1 on β-catenin transcriptional activity. Reductions in SAP97 abundance also decrease GSK3β phosphorylation. In addition, we find that over expression of DISC1 leads to an increase in the abundance of SAP97, by inhibiting its proteasomal degradation. Our findings suggest that SAP97 and DISC1 contribute to maintaining Wnt/β-catenin signaling activity within a homeostatic range by regulating GSK3β phosphorylation.

Keywords: DISC1; SAP97; Wnt; autism; schizophrenia; β-catenin.

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism*
Discs Large Homolog 1 Protein
Glycogen Synthase Kinase 3 beta / metabolism*
HEK293 Cells
Humans
Membrane Proteins / metabolism*
Nerve Tissue Proteins / metabolism*
Phosphorylation
Wnt Signaling Pathway*

Substances

Adaptor Proteins, Signal Transducing
DISC1 protein, human
DLG1 protein, human
Discs Large Homolog 1 Protein
Membrane Proteins
Nerve Tissue Proteins
GSK3B protein, human
Glycogen Synthase Kinase 3 beta

Abstract

MeSH terms

Substances

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