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Syntenin: PDZ Protein Regulating Signaling Pathways and Cellular Functions - PubMed

  • ️Tue Jan 01 2019

Review

Syntenin: PDZ Protein Regulating Signaling Pathways and Cellular Functions

Tadayuki Shimada et al. Int J Mol Sci. 2019.

Abstract

Syntenin is an adaptor-like molecule that has two adjacent tandem postsynaptic density protein 95/Discs large protein/Zonula occludens 1 (PDZ) domains. The PDZ domains of syntenin recognize multiple peptide motifs with low to moderate affinity. Many reports have indicated interactions between syntenin and a plethora of proteins. Through interactions with various proteins, syntenin regulates the architecture of the cell membrane. As a result, increases in syntenin levels induce the metastasis of tumor cells, protrusion along the neurite in neuronal cells, and exosome biogenesis in various cell types. Here, we review the updated data that support various roles for syntenin in the regulation of neuronal synapses, tumor cell invasion, and exosome control.

Keywords: exosome biogenesis; membrane architecture; synapse; syntenin; tumor metastasis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1

Structural character of syntenin and PDZ domain. (A) Schematic illustration of the domain structure of syntenin. The N-terminal domain (NTD), the PDZ domain tandem repeat, and the C-terminal domain (CTD) of syntenin are indicated. The names of representative syntenin-binding proteins are shown beneath the domains required for their interaction. Neurexin showed controversial results, preferentially binding with PDZ1 or PDZ2, and CD63 requires both the CTD and PDZ1 for interaction. IL-5Rα can interact with both PDZ1 and PDZ2. (B) Ribbon diagram of the syntenin PDZ2 domain bound to the C-terminal peptide of syndecan-4 (TNEFYA) (yellow line diagram) (left). Surface representation of the syntenin PDZ2 domain showing three hydrophobic pockets and the syndecan-4 peptide (white bar) (right). Circles indicate three binding pockets. The three C-terminal residues are shown in Cα race. The side chains of tyrosine (−1) and phenylalanine (−2) occupy the two pockets S−1 and S−2, and alanine (0) occupies S0. Images and the legend are from Kang et al. [18]. (C) Domain organizations of PDZ proteins mentioned in this review. PDZ domains are shown in orange ellipses. Other domains are indicated: CaM Kinase, calmodulin-dependent kinase (CaMK)-like domain; GuK, guanylate kinase-like domain; L27, domain initially found in LIN2 and LIN7; SH3, Src homology 3 domain.

Figure 2
Figure 2

Syntenin is involved in dendritic spine morphology and memory impairment in tuberous sclerosis complex (TSC) model rats (A) Model depicting the role of syntenin in spine and shaft synapse formation. In wild-type neurons, Rheb-guanosine diphosphate (GDP) interacts with syntenin, promoting syntenin degradation. This decrease in syntenin levels facilitates the association of CASK with syndecan, leading to normal spine development (left). However, Tsc gene mutation increases the level of Rheb-guanosine triphosphate (GTP), which rescues syntenin from degradation. The accumulated syntenin inhibits the binding of CASK to syndecan and associates with ephrinB3, resulting in impaired spine formation and enhanced shaft synapse formation (right). Syntenin also mediates the translocation of syndecan from the recycling endosome to the cell surface (black arrows). (B) Representative images of dendrites of cultured rat wild-type and Tsc2+/− neurons transfected with an enhanced green fluorescent protein (EGFP) plasmid and with syntenin small interfering RNA (siRNA) or scrambled siRNA. Elongated spines in Tsc2+/− neurons are restored to normal morphology by the knockdown of syntenin. The neurons were immunolabelled with anti-vGlut1 (red). Scale bar, 5 μm. (C) Tsc2+/− rats (Eker rats) showed contextual memory deficits, but knockdown of syntenin expression in the brain reversed their memory impairment. Schematic illustration of the contextual fear discrimination test (top). Quantification of the freezing time in each condition is shown (bottom).

Figure 3
Figure 3

Syntenin-mediated signaling in the regulation of membrane structure and cell motility. (A) Syntenin facilitates the motility and metastasis of tumor cells. Syntenin activates the focal adhesion kinase (FAK)-c-Src kinase complex and induces the degradation of Inhibitor kappa B Iκ-B, resulting in the translocation of nuclear factor-kappa B (NF-κB) into the nucleus. Consequently, NF-κB induces the gene expression of matrix-metalloprotease (MMP)-2, ras homolog gene family, member A (RhoA), and cell division control protein (Cdc)42, inducing the degradation of the extracellular matrix and increasing cell motility by F-actin regulation. (B) Schematic illustration of representative cell shapes and F-actin rearrangement in breast cancer cells upon syntenin RNA interference (RNAi) treatment. The images refer to Menezes et al. [60]. (C) Syntenin binds to the cytoplasmic tail of activated leukocyte cell adhesion molecule (ALCAM) and strengthens the binding by coupling ALCAM to the actin cortex. Ezrin also connects some of the ALCAM molecules to actin at juxtamembrane sites. Upon binding of ALCAM to its ligand cluster of differentiation (CD)6, the complex is strengthened, and syntenin as well as ezrin can be phosphorylated, leading to outside-in signaling and ultimately to cellular responses, most likely adhesion strengthening. (D) Model of the CD63-syntenin-ALIX-dependent trafficking of human papillomaviruses (HPV). Its endocytosis occurs at the CD63-enriched microdomains of plasma membrane. Virus uptake starts with recruitment of syntenin and ALG-2 interacting protein X (ALIX) at early endosomes. The CD63-syntenin-ALIX complex promotes post-endocytic trafficking of HPV to multivesicular bodies. (E) Syntenin-ALIX complex is involved in exosome biogenesis and release. Syntenin associates with syndecan and CD63 in exosomes, and promotes their releases. Biogenesis is enhanced by interaction between ALIX and Src, which phosphorylates syndecan and syntenin. (F) Syntenin works as an adaptor protein for Unc51.1, SynGAP, and Rab5. Unc51.1 activates SynGAP and downregulates Rab5 activity, resulting in inhibition of the early endosome pathway and the promotion of neurite extension. (G) Syntenin-mediates anoikis-resistance. Syntenin can activate PKCα in an FAK-dependent manner, and induce Bcl-2 phosphorylation. This signaling promotes anti-apoptotic protective autophagy instead of toxic autophagy.

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