Syndecans as cell surface receptors: Unique structure equates with functional diversity

Choi, Youngsil; Chung, Heesung; Jung, Heyjung; Couchman, John R.; Oh, Eok Soo

doi:10.1016/j.matbio.2010.10.006

Cited by 147 publications

(132 citation statements)

References 119 publications

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“…In the larger view of intracellular pathogens, it is worth emphasizing that Chlamydia and Neisseria spp., as well as viruses from the families Retroviridae, Herpesviridae, Flaviviridae, and Picornaviridae interact with HSPGs at the cell surface (87,88). Chlamydia trachomatis, cytomegalovirus, herpes simplex virus, hepatitis C virus, and others activate GFR pathways, in many cases bridging via soluble factors (89)(90)(91)(92)(93).…”

Section: Discussionmentioning

confidence: 99%

Annexin A2 and S100A10 Regulate Human Papillomavirus Type 16 Entry and Intracellular Trafficking in Human Keratinocytes

Dziduszko

Ozbun

2013

J Virol

125

143

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Human papillomaviruses (HPVs) cause benign and malignant tumors of the mucosal and cutaneous epithelium. The initial events regulating HPV infection impact the establishment of viral persistence, which is requisite for malignant progression of HPV-infected lesions. However, the precise mechanisms involved in HPV entry into host cells, including the cellular factors regulating virus uptake, are not clearly defined. We show that HPV16 exposure to human keratinocytes initiates epidermal growth factor receptor (EGFR)-dependent Src protein kinase activation that results in phosphorylation and extracellular translocation of annexin A2 (AnxA2). HPV16 particles interact with AnxA2 in association with S100A10 as a heterotetramer at the cell surface in a Ca 2؉ -dependent manner, and the interaction appears to involve heparan-sulfonated proteoglycans. We show multiple lines of evidence that this interaction promotes virus uptake into host cells. An antibody to AnxA2 prevents HPV16 internalization, whereas an antibody to S100A10 blocks infection at a late endosomal/lysosomal site. These results suggest that AnxA2 and S100A10 have separate roles during HPV16 binding, entry, and trafficking. Our data additionally imply that AnxA2 and S100A10 may be involved in regulating the intracellular trafficking of virus particles prior to nuclear delivery of the viral genome.

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Section: Discussionmentioning

confidence: 99%

Annexin A2 and S100A10 Regulate Human Papillomavirus Type 16 Entry and Intracellular Trafficking in Human Keratinocytes

Dziduszko

Ozbun

2013

J Virol

125

143

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“…HSPGs consist of a cell surface or matrix protein with covalently attached heparan sulfate (HS) glycosaminoglycans, and they regulate a wide variety of biological activities as well as functioning as binding receptors for a multitude of viral and bacterial pathogens (48)(49)(50). Among the HSPGs, syndecan-1, which consists of a single transmembrane (type 1) core domain with an ectodomain that carries three to five HS chains (51), is the most prevalent in keratinocytes and its expression is increased during wound healing (52).…”

Section: Hpv16 Binding and Entrymentioning

confidence: 99%

The Evolving Field of Human Papillomavirus Receptor Research: a Review of Binding and Entry

Raff

Woodham

Raff

et al. 2013

J Virol

159

149

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Human papillomaviruses (HPVs) infect epithelia and can lead to the development of lesions, some of which have malignant potential. HPV type 16 (HPV16) is the most oncogenic genotype and causes various types of cancer, including cervical, anal, and head and neck cancers. However, despite significant research, our understanding of the mechanism by which HPV16 binds to and enters host cells remains fragmented. Over several decades, many HPV receptors and entry pathways have been described. This review puts those studies into context and offers a model of HPV16 binding and entry as a framework for future research. Our model suggests that HPV16 binds to heparin sulfate proteoglycans (HSPGs) on either the epithelial cell surface or basement membrane through interactions with the L1 major capsid protein. Growth factor receptors may also become activated through HSPG/growth factor/HPV16 complexes that initiate signaling cascades during early virion-host cell interactions. After binding to HSPGs, the virion undergoes conformational changes, leading to isomerization by cyclophilin B and proprotein convertasemediated L2 minor capsid protein cleavage that increases L2 N terminus exposure. Along with binding to HSPGs, HPV16 binds to ␣6 integrins, which initiate further intracellular signaling events. Following these primary binding events, HPV16 binds to a newly identified L2-specific receptor, the annexin A2 heterotetramer. Subsequently, clathrin-, caveolin-, lipid raft-, flotillin-, cholesterol-, and dynamin-independent endocytosis of HPV16 occurs. Since the discovery of human papillomaviruses (HPVs), researchers in the field have sought to identify the mechanism by which these viruses enter host cells. Although much work has been done to date and many possible receptors have been identified, a clearly defined description of the entry of HPVs has remained controversial. In many cases of viral infection, our understanding of simple binding and uptake through a singular mechanism has given way to a model of a more complex interaction between several specific receptors, coreceptors, and cofactors (1-3). The purpose of this review is to synthesize the known data regarding HPV type 16 (HPV16) binding proteins at the cell surface, and their associated molecules, and attempt to connect them, if possible, into a testable framework of binding and entry. Due to the fact that HPVs are a diverse group of over 150 viruses, this review focuses primarily on the most common of the cancer-causing genotypes, HPV16, while making it clear when non-HPV16 genotypes are reviewed. The development of several HPV particle production systems has allowed researchers to begin to delineate the mechanisms behind viral entry; however, important differences between particles developed in vitro made direct comparisons challenging. Therefore, not only HPV16 structure but also the multiple forms the virus structure takes in the laboratory are discussed below. Finally, due to the tropism of HPV16 for human epithelial cells during a natural infection, this rev...

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“…Its heparan sulfate (HS) chains and core protein could control the stability, movement and reception of diffusible heparin-binding growth factors (1). In addition, it can form physical connections between the extracellular matrix (ECM) and intracellular signaling to affect the growth and differentiation of a number of tissues and organs (2,3).…”

Section: Introductionmentioning

confidence: 99%

Expression and roles of syndecan-4 in dental epithelial cell differentiation

Zhang

Yang

Sun

et al. 2014

International Journal of Molecular Medicine

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Abstract. Syndecan-4 (SDC4), a transmembrane heparan sulfate proteoglycan, acts as a signal transducer. It affects the growth and differentiation of a number of tissues and organs. However, the specific mechanisms through which SDC4 regulates the differentiation of dental epithelial cells (amelogenesis) and tooth development remains largely unknown. In the present study, to identify the SDC4-regulated processes in dental epithelial cells, the SDC4 expression pattern was examined in mouse molar and postnatal incisor tooth germs during the late bell stage of development. Small interfering RNA (siRNA) was designed for this study and used to downregulate SDC4 expression in the rat dental epithelial cell line, HAT-7. The results revealed that SDC4 was mainly present in the oral epithelium, the dental epithelial cells of enamel organs in the molars and the cervical loops in the incisors. When the inner enamel epithelial cells gave rise to ameloblasts, however, the loss of SDC4 expression was evident. SDC4 was also expressed in stratum intermedium (SI) cells in the incisors and in dental mesenchymal cells adjacent to the cervical loops in molars (E18) and postnatal incisors. Fibroblast growth factor 10 (FGF10) promoted proliferation and slightly decreased cell differentiation. The knockdown of SDC4 using specific siRNA led to a decrease in cell proliferation and a highly significant increase in amelogenin, ameloblastin, kallikrein 4 and matrix metalloproteinase 20 expression, molecules that are known to participate in the formation of enamel. These effects were attenuated by FGF10, which upregulated SDC4 expression. Taken together, these results suggest that SDC4 participates in amelogenesis, and FGF10 may modulate dental epithelial cell behaviors through the regulation of SDC4 expression. IntroductionSyndecan (SDC)4 is a cell surface heparan sulfate proteoglycan (HSPG). Its heparan sulfate (HS) chains and core protein could control the stability, movement and reception of diffusible heparin-binding growth factors (1). In addition, it can form physical connections between the extracellular matrix (ECM) and intracellular signaling to affect the growth and differentiation of a number of tissues and organs (2,3). SDC4 is highly complex by virtue of its external side chains, and thus interacts with a variety of ligands, such as vascular endothelial growth factors (VEGFs), platelet-derived growth factors (PDGFs) and fibroblast growth factors (FGFs) (4). At the cell membrane, SDC4 stabilizes the interactions between ligands and receptors by forming a ternary complex, which has been demonstrated in several signaling pathways (5,6). Proteolytic cleavage and shedding of its extracellular domain can spread FGF signaling to adjacent cells, thus regulating the local reception of FGF signaling activity (7). Its cytoplasmic domains can also initiate FGF-induced signaling independently of FGFRs through the activation of Rho GTPases, such as Rac1, which plays an essential role in the dental epithelium, involving cell-matrix interactio...

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Syndecans as cell surface receptors: Unique structure equates with functional diversity

Cited by 147 publications

References 119 publications

Annexin A2 and S100A10 Regulate Human Papillomavirus Type 16 Entry and Intracellular Trafficking in Human Keratinocytes

Annexin A2 and S100A10 Regulate Human Papillomavirus Type 16 Entry and Intracellular Trafficking in Human Keratinocytes

The Evolving Field of Human Papillomavirus Receptor Research: a Review of Binding and Entry

Expression and roles of syndecan-4 in dental epithelial cell differentiation

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