A triple serine motif in the intracellular domain of SorCS2 impacts its cellular signaling
Summary: The Vps10p-domain receptors SorCS1-3 have been repeatedly associated with the development of neurological and psychiatric disorders. They have emerged as key regulators of synaptic activity and neurotrophic signaling, but the underlying molecular mechanism remains poorly understood. Here we...
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Elsevier
2025-06-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004225009563 |
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| author | Anders Dalby Mathias Kaas Lars Meinertz Byg Signe Bundgaard Christiansen Christian M. Longworth Simon Bøggild Hansen Per Qvist Jens R. Nyengaard Peder Madsen Simon Mølgaard Simon Glerup |
| author_facet | Anders Dalby Mathias Kaas Lars Meinertz Byg Signe Bundgaard Christiansen Christian M. Longworth Simon Bøggild Hansen Per Qvist Jens R. Nyengaard Peder Madsen Simon Mølgaard Simon Glerup |
| author_sort | Anders Dalby |
| collection | DOAJ |
| description | Summary: The Vps10p-domain receptors SorCS1-3 have been repeatedly associated with the development of neurological and psychiatric disorders. They have emerged as key regulators of synaptic activity and neurotrophic signaling, but the underlying molecular mechanism remains poorly understood. Here we report that the SorCS2 intracellular domain (ICD) contains a triple serine motif that potentially functions as a signaling switch to induce intracellular signaling in hippocampal neurons. We show, that serine to alanine substitution in this motif renders neurons less responsive to BDNF, whereas phosphomimetic mutations induce neurotrophic effects independently of the SorCS2 extracellular domain (ECD) and BDNF. Hence, we develop triple serine motif-based cell-penetrating peptides that modulate distinct intracellular signaling, partially overlapping with the BDNF pathway, ultimately activating the transcription factor CREB. Taken together, we provide insights into SorCS2 mediated neurotrophic signaling and use this knowledge to develop pharmacologically active molecules. |
| format | Article |
| id | doaj-art-2dca0cae1d904ccc9dfa56d7ceeabcc4 |
| institution | DOAJ |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-2dca0cae1d904ccc9dfa56d7ceeabcc42025-08-20T03:18:32ZengElsevieriScience2589-00422025-06-0128611269510.1016/j.isci.2025.112695A triple serine motif in the intracellular domain of SorCS2 impacts its cellular signalingAnders Dalby0Mathias Kaas1Lars Meinertz Byg2Signe Bundgaard Christiansen3Christian M. Longworth4Simon Bøggild Hansen5Per Qvist6Jens R. Nyengaard7Peder Madsen8Simon Mølgaard9Simon Glerup10Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark; Teitur Trophics ApS, 8200 Aarhus, DenmarkDepartment of Biomedicine, Aarhus University, 8000 Aarhus, Denmark; Teitur Trophics ApS, 8200 Aarhus, DenmarkDepartment of Biomedicine, Aarhus University, 8000 Aarhus, DenmarkDepartment of Biomedicine, Aarhus University, 8000 Aarhus, DenmarkDepartment of Biomedicine, Aarhus University, 8000 Aarhus, DenmarkDepartment of Biomedicine, Aarhus University, 8000 Aarhus, DenmarkDepartment of Biomedicine, Aarhus University, 8000 Aarhus, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, 8210 Aarhus, Denmark; Centre for Integrative Sequencing, iSEQ, Aarhus University, 8000 Aarhus, Denmark; Centre for Genomics and Personalized Medicine, CGPM, Aarhus University, 8200 Aarhus, DenmarkCore Center for Molecular Morphology, Section for Stereology and Microscopy, Department of Clinical Medicine, Aarhus University, 8200 Aarhus, Denmark; Department of Pathology, Aarhus University Hospital, 8200 Aarhus, DenmarkDepartment of Biomedicine, Aarhus University, 8000 Aarhus, DenmarkDepartment of Biomedicine, Aarhus University, 8000 Aarhus, Denmark; Teitur Trophics ApS, 8200 Aarhus, Denmark; Corresponding authorDepartment of Biomedicine, Aarhus University, 8000 Aarhus, Denmark; Teitur Trophics ApS, 8200 Aarhus, Denmark; Corresponding authorSummary: The Vps10p-domain receptors SorCS1-3 have been repeatedly associated with the development of neurological and psychiatric disorders. They have emerged as key regulators of synaptic activity and neurotrophic signaling, but the underlying molecular mechanism remains poorly understood. Here we report that the SorCS2 intracellular domain (ICD) contains a triple serine motif that potentially functions as a signaling switch to induce intracellular signaling in hippocampal neurons. We show, that serine to alanine substitution in this motif renders neurons less responsive to BDNF, whereas phosphomimetic mutations induce neurotrophic effects independently of the SorCS2 extracellular domain (ECD) and BDNF. Hence, we develop triple serine motif-based cell-penetrating peptides that modulate distinct intracellular signaling, partially overlapping with the BDNF pathway, ultimately activating the transcription factor CREB. Taken together, we provide insights into SorCS2 mediated neurotrophic signaling and use this knowledge to develop pharmacologically active molecules.http://www.sciencedirect.com/science/article/pii/S2589004225009563Molecular biologyMolecular neuroscience |
| spellingShingle | Anders Dalby Mathias Kaas Lars Meinertz Byg Signe Bundgaard Christiansen Christian M. Longworth Simon Bøggild Hansen Per Qvist Jens R. Nyengaard Peder Madsen Simon Mølgaard Simon Glerup A triple serine motif in the intracellular domain of SorCS2 impacts its cellular signaling iScience Molecular biology Molecular neuroscience |
| title | A triple serine motif in the intracellular domain of SorCS2 impacts its cellular signaling |
| title_full | A triple serine motif in the intracellular domain of SorCS2 impacts its cellular signaling |
| title_fullStr | A triple serine motif in the intracellular domain of SorCS2 impacts its cellular signaling |
| title_full_unstemmed | A triple serine motif in the intracellular domain of SorCS2 impacts its cellular signaling |
| title_short | A triple serine motif in the intracellular domain of SorCS2 impacts its cellular signaling |
| title_sort | triple serine motif in the intracellular domain of sorcs2 impacts its cellular signaling |
| topic | Molecular biology Molecular neuroscience |
| url | http://www.sciencedirect.com/science/article/pii/S2589004225009563 |
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