Theranostics 2018; 8(14):3977-3990. doi:10.7150/thno.22274

Research Paper

The S100A4 Protein Signals through the ErbB4 Receptor to Promote Neuronal Survival

Stanislava Pankratova1,2, Jorg Klingelhofer1, Oksana Dmytriyeva1,3, Sylwia Owczarek1, Alexander Renziehausen4, Nelofer Syed4, Alexandra E. Porter5, David T. Dexter6, Darya Kiryushko5,6✉

1. Laboratory of Neural Plasticity, Department of Neuroscience, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark
2. Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark
3. Research Laboratory for Stereology and Neuroscience, Bispebjerg Hospital, Bispebjerg Bakke 23, 2400 Copenhagen, Denmark
4. John Fulcher Neuro-Oncology Laboratory, Imperial College London, Hammersmith Hospital Campus, Burlington Danes Building, 160 Du Cane Road, W12 0NN London, UK
5. Department of Materials and London Center for Nanotechnology, Imperial College, Exhibition Road, SW72AZ London, UK
6. Center for Neuroinflammation and Neurodegeneration, Imperial College London, Hammersmith Hospital Campus, Burlington Danes Building, 160 Du Cane Road, W12 0NN London, UK

Abstract

Understanding the mechanisms of neurodegeneration is crucial for development of therapies to treat neurological disorders. S100 proteins are extensively expressed in the injured brain but S100's role and signalling in neural cells remain elusive. We recently demonstrated that the S100A4 protein protects neurons in brain injury and designed S100A4-derived peptides mimicking its beneficial effects. Here we show that neuroprotection by S100A4 involves the growth factor family receptor ErbB4 and its ligand Neuregulin 1 (NRG), key regulators of neuronal plasticity and implicated in multiple brain pathologies. The neuroprotective effect of S100A4 depends on ErbB4 expression and the ErbB4 signalling partners ErbB2/Akt, and is reduced by functional blockade of NRG/ErbB4 in cell models of neurodegeneration. We also detect binding of S100A4 with ErbB1 (EGFR) and ErbB3. S100A4-derived peptides interact with, and signal through ErbB, are neuroprotective in primary and immortalized dopaminergic neurons, and do not affect cell proliferation/motility - features which make them promising as potential neuroprotectants. Our data suggest that the S100-ErbB axis may be an important mechanism regulating neuronal survival and plasticity.

Keywords: S100, S100A4, ErbB, neuroprotection, peptide

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How to cite this article:
Pankratova S, Klingelhofer J, Dmytriyeva O, Owczarek S, Renziehausen A, Syed N, Porter AE, Dexter DT, Kiryushko D. The S100A4 Protein Signals through the ErbB4 Receptor to Promote Neuronal Survival. Theranostics 2018; 8(14):3977-3990. doi:10.7150/thno.22274. Available from http://www.thno.org/v08p3977.htm