TY - JOUR
T1 - A triple serine motif in the intracellular domain of SorCS2 impacts its cellular signaling
AU - Dalby, Anders
AU - Kaas, Mathias
AU - Meinertz Byg, Lars
AU - Christiansen, Signe Bundgaard
AU - Longworth, Christian M.
AU - Hansen, Simon Bøggild
AU - Qvist, Per
AU - Nyengaard, Jens R.
AU - Madsen, Peder
AU - Mølgaard, Simon
AU - Glerup, Simon
N1 - Publisher Copyright:
© 2025 The Authors
PY - 2025/6
Y1 - 2025/6
N2 - 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.
AB - 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.
KW - Molecular biology
KW - Molecular neuroscience
UR - http://www.scopus.com/inward/record.url?scp=105006894335&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2025.112695
DO - 10.1016/j.isci.2025.112695
M3 - Journal article
AN - SCOPUS:105006894335
SN - 2589-0042
VL - 28
JO - iScience
JF - iScience
IS - 6
M1 - 112695
ER -