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

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.

Urine and serum S100A8/A9 and S100A12 associate with active lupus nephritis and may predict response to rituximab treatment

“…Indeed, S100 proteins act in an autocrine and paracrine manner amplifying inflammatory signals in the tissue microenvironment. [31][32][33][34] Since S100 proteins are primarily expressed by innate immune cells, namely neutrophils and monocytes/macrophages, that recruit to inflamed tissues including the kidneys in SLE, [16][17][18] local production may only partially translate to different serum protein levels between patients with milder versus more severe inflammatory activity in SLE.…”

CD146, from a melanoma cell adhesion molecule to a signaling receptor

“…[138][139][140][141] The secreted S100 proteins bind with several cell-surface receptors, including advanced glycation end products (RAGE), [142][143][144][145][146] toll-like receptor 4 (TLR4), 147 CD36, 148 FGFR1, 149 ALCAM, 150 CD68, 151 and ErbB4. 152 However, how the cell-surface receptors mediate extracellular S100 signaling is lacking and how S100 protein secretion is dynamically regulated in biological processes also still remains unknown.…”

Molecular rotors report on changes in live cell plasma membrane microviscosity upon interaction with beta-amyloid aggregates

“…84 As we have previously shown, both S100A4 and H3 protect neurons from apoptosis and oxidative stress in vitro and in animal models of brain trauma, epilepsy and nerve degeneration. 84,85 These effects are mediated by several plasma membrane receptors triggering intracellular signalling cascades 84,86 ; however, the effect of S100A4 or its derivatives on biophysical properties of cell membranes has not yet been investigated. We therefore tested whether treatment with the neuroprotective H3 peptide affects membrane microviscosity of non-treated and/or Aβ-treated SH-SY5Y cells.…”

“…Like its parent protein S100A4, the H3 peptide is a multimeric molecule and was synthetized as a tetramer consisting of four identical peptide chains attached to a lysine backbone. H3 binds to its plasma membrane targets with nanomolar to low micromolar affinity and low dissociation rate 84,86 and could thus cluster cell surface receptors initiating 'background' pro-survival signalling and/or increasing membrane stability. Additionally, H3 could be internalised together with its binding partners and exert its biological effects acting from the cytoplasm, as S100A4 is known to bind intracellular targets that regulate cytoskeleton dynamics, thereby affecting cell morphology and motility.…”