Versican G3 Domain Regulates Neurite Growth and Synaptic Transmission of Hippocampal Neurons by Activation of Epidermal Growth Factor Receptor

Abstract

Versican is one of the major extracellular matrix (ECM) proteins in the brain. ECM molecules and their cleavage products critically regulate the growth and arborization of neurites, hence adjusting the formation of neural networks. Recent findings have revealed that peptide fragments containing the versican C terminus (G3 domain) are present in human brain astrocytoma. The present study demonstrated that a versican G3 domain enhanced cell attachment, neurite growth, and glutamate receptor-mediated currents in cultured embryonic hippocampal neurons. In addition, the G3 domain intensified dendritic spines, increased the clustering of both synaptophysin and the glutamate receptor subunit GluR2, and augmented excitatory synaptic activity. In contrast, a mutated G3 domain lacking the epidermal growth factor (EGF)-like repeats (G3⌬EGF) had little effect on neurite growth and glutamatergic function. Treating the neurons with the G3-conditioned medium rapidly increased the levels of phosphorylated EGF receptor (pEGFR) and phosphorylated extracellular signal-regulated kinase (pERK), indicating an activation of EGFR-mediated signaling pathways. Blockade of EGFR prevented the G3-induced ERK activation and suppressed the G3-provoked enhancement of neurite growth and glutamatergic function but failed to block the G3-mediated enhancement of cell attachment. These combined results indicate that the versican G3 domain regulates neuronal attachment, neurite outgrowth, and synaptic function of hippocampal neurons via EGFR-dependent and -independent signaling pathway(s). Our findings suggest a role for ECM proteolytic products in neural development and regeneration.

The Proteoglycan Brevican Binds to Fibronectin after Proteolytic Cleavage and Promotes Glioma Cell Motility

“…Additionally, these authors demonstrated that versican isoforms could increase EGFR levels in glioma cells and signal through EGFR activation in neural cells (35)(36)(37). This prompted us to investigate whether EGFR signaling could mediate the brevican-dependent increase of fibronectin in our model.…”

Expression of Versican V3 by Arterial Smooth Muscle Cells Alters Tumor Growth Factor β (TGFβ)-, Epidermal Growth Factor (EGF)-, and Nuclear Factor κB (NFκB)-dependent Signaling Pathways, Creating a Microenvironment That Resists Monocyte Adhesion

“…Furthermore, V3-expressing ASMCs had reduced levels of PI3K p85 downstream of EGFR, indicating that the blockade of EGFR-dependent signaling may be partially due to decreases in signaling mediators. Because V3 has EGF-like motifs that have been shown to affect EGF-dependent signaling pathways (72)(73)(74), the blockade of EGFR-dependent signaling might be mediated by the G3 domain within V3. These possibilities are currently under investigation.…”

Activation of Mouse Cumulus-Oocyte Complex Maturation In Vitro Through EGF-Like Activity of Versican1

“…Versican protein has a complex structure, including a highaffinity hyaluronan binding N-terminal domain, a densely chondroitin sulfate substituted midsection, and cell surface receptor-interacting functions, including reported abilities to activate toll-like receptors [27][28][29] and the EGFR [30][31][32]. Versican is widely expressed and mainly involved in tissue morphogenic processes, such as heart valve and limb morphogenesis [33][34][35], but it also promotes growth and metastasis of a range of carcinoma types [36].…”