Publication
A triple serine motif in the intracellular domain of SorCS2 impacts its cellular signaling
In this iScience paper, Dalby et al. uncover a signalling mechanism within the SorCS2 receptor that regulates neuronal responses to BDNF. Using bit.bio's ioGlutamatergic Neurons alongside primary mouse neurons, the team identifies a conserved triple-serine motif in the SorCS2 intracellular domain that functions as a molecular switch for neurotrophic signaling. Mutation of this motif disrupted BDNF-induced MAPK activation and neurite branching, while phosphomimetic variants or peptides mimicking the motif activated CREB and induced neurotrophic effects independently of BDNF. The findings highlight SorCS2 as a modulator of neuronal survival and differentiation, and demonstrate how ioCells can be used to study intracellular signaling and neurotrophic pathway modulation.
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In this iScience paper, Dalby et al. uncover a signalling mechanism within the SorCS2 receptor that regulates neuronal responses to BDNF. Using bit.bio's ioGlutamatergic Neurons alongside primary mouse neurons, the team identifies a conserved triple-serine motif in the SorCS2 intracellular domain that functions as a molecular switch for neurotrophic signaling. Mutation of this motif disrupted BDNF-induced MAPK activation and neurite branching, while phosphomimetic variants or peptides mimicking the motif activated CREB and induced neurotrophic effects independently of BDNF. The findings highlight SorCS2 as a modulator of neuronal survival and differentiation, and demonstrate how ioCells can be used to study intracellular signaling and neurotrophic pathway modulation.
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.
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