Trans-regulation of Syndecan Functions by Hetero-oligomerization

Choi, Youngsil; Kwon, Mi Jung; Lim, Yeunhwan; Yun, Ji Hye; Lee, Weontae; Oh, Eok Soo

doi:10.1074/jbc.m114.611798

Cited by 21 publications

(22 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because this TMD also mediates heteromeric interactions of syndecans, we investigated whether Phe-169 could regulate SDS-resistant heterodimer formation. Consistent with a previous report (19), we found that wild-type syndecan-2 (SDC2) and a syndecan-4 mutant (4eTC) formed SDS-resistant heterodimers, whereas the S2(F169Y) mutant showed reduced SDS-resistant heterodimer formation with 4eTC compared with the S2(F172Y) mutant or SDC2 wild type (Fig. 1C).…”

Section: Resultssupporting

confidence: 81%

“…The Conserved Phenylalanine Regulates SDS-resistant Heterodimer Formation of Syndecan-2-We have reported previously that syndecan-2 and -4 formed SDS-resistant heterodimers through the GXXXG motif in their TMDs (19) and that the unique phenylalanine (Phe-167) on the TMD of syndecan-2 strengthened its homodimerization (27). In addition to Phe-167, the syndecan-2 TMD contains additional phenylalanines near the GXXXG motif.…”

Section: Resultsmentioning

confidence: 99%

“…The Conserved Phenylalanine Regulates Heterodimerizationmediated Syndecan-2 and -4 Functions-Because our research group has shown that increased heterodimerization, which disrupts homo-oligomerization, inhibits individual functions of syndecans (19), we expected that a change in the ability to heterodimerize may alter the function of heterodimers. To investigate this possibility, we examined whether altering heterodimer formation affected syndecan-2-mediated tumorigenic signal transduction.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, the GXXXG motifmediated interactions of syndecans are important in regulating syndecan functions in cells (17). Syndecan family members can also form SDS-resistant heterodimers in vitro and in vivo through binding of their GXXXG motifs (18,19). Furthermore, we have reported recently that the hetero-oligomerization between syndecan-2 and -4 reduces the activities mediated by these proteins (19).…”

mentioning

confidence: 99%

“…Syndecan family members can also form SDS-resistant heterodimers in vitro and in vivo through binding of their GXXXG motifs (18,19). Furthermore, we have reported recently that the hetero-oligomerization between syndecan-2 and -4 reduces the activities mediated by these proteins (19). However, although previous findings have shown that the expression patterns of individual syndecans are regulated differently in individual cells and tissue types (20,21) and that syndecan hetero-oligomerization in cell membranes may be important in several diseases and cancers, relatively little is known about the mechanisms underlying hetero-oligomerization of syndecan family members.…”

mentioning

confidence: 99%

See 4 more Smart Citations

The Conserved Phenylalanine in the Transmembrane Domain Enhances Heteromeric Interactions of Syndecans

Kwon

Park

Jang

et al. 2016

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

The transmembrane domain (TMD) of the syndecans, a family of transmembrane heparin sulfate proteoglycans, is involved in forming homo-and heterodimers and oligomers that transmit signaling events. Recently, we reported that the unique phenylalanine in TMD positively regulates intramolecular interactions of syndecan-2. Besides the unique phenylalanine, syndecan-2 contains a conserved phenylalanine (SDC2-Phe-169) that is present in all syndecan TMDs, but its function has not been determined. We therefore investigated the structural role of SDC2-Phe-169 in syndecan TMDs. Replacement of SDC2-Phe-169 by tyrosine (S2F169Y) did not affect SDS-resistant homodimer formation but significantly reduced SDS-resistant heterodimer formation between syndecan-2 and -4, suggesting that SDC2-Phe-169 is involved in the heterodimerization/ oligomerization of syndecans. Similarly, in an in vitro binding assay, a syndecan-2 mutant (S2(F169Y)) showed a significantly reduced interaction with syndecan-4. FRET assays showed that heteromolecular interactions between syndecan-2 and -4 were reduced in HEK293T cells transfected with S2(F169Y) compared with syndecan-2. Moreover, S2(F169Y) reduced downstream reactions mediated by the heterodimerization of syndecan-2 and -4, including Rac activity, cell migration, membrane localization of PKC␣, and focal adhesion formation. The conserved phenylalanine in syndecan-1 and -3 also showed heterodimeric interaction with syndecan-2 and -4. Taken together, these findings suggest that the conserved phenylalanine in the TMD of syndecans is crucial in regulating heteromeric interactions of syndecans.Integral membrane receptors consist of an extracellular domain that binds specific ligands, a transmembrane domain (TMD) 2 that transmits signals in response to ligand binding, and a cytoplasmic domain to which the signals are transmitted by the TMD and that is thereby activated, resulting in a conformational change that causes binding or induction of enzymatic activity inside the cell (1, 2). The TMD is therefore critically important in transmitting signals from the external environment to the inside of the cell, with many recent investigations exploring the mechanism by which TMD interactions regulate cell signaling (2-6). TMDs of single-pass membrane receptors have been shown to cluster, resulting in homotypic and/or heterotypic interactions, with TMDs often forming not only homo-and/or heterodimers but higher-order oligomers in cell membranes (7-10). Most investigations of TMD interactions have analyzed homo-oligomerization in vitro and in vivo, with fewer to date assessing heterotypic TMD associations.One of the most investigated examples of hetero-oligomerization in biology involves the family of EGF receptors, also called the ErbB family (11-13). Although only four ErbB family members have been identified to date, ErbB1 (EGF receptor), ErbB2 (HER2, Neu), ErbB3 (HER3), and ErbB4 (HER4), they have been shown to form 28 homo-and heterodimers (12). These combinations are thought to result in diverse cellul...

show abstract

Section: Resultssupporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

The Conserved Phenylalanine in the Transmembrane Domain Enhances Heteromeric Interactions of Syndecans

Kwon

Park

Jang

et al. 2016

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

Minireview: Syndecans and their crucial roles during tissue regeneration

Chung

Multhaupt

et al. 2016

FEBS Letters

Self Cite

View full text Add to dashboard Cite

Syndecans are transmembrane heparan sulfate proteoglycans, with roles in development, tumorigenesis and inflammation, and growing evidence for involvement in tissue regeneration. This is a fast developing field with the prospect of utilizing tissue engineering and biomaterials in novel therapies. Syndecan receptors are not only ubiquitous in mammalian tissues, regulating cell adhesion, migration, proliferation, and differentiation through independent signaling but also working alongside other receptors. Their importance is highlighted by an ability to interact with a diverse array of ligands, including extracellular matrix glycoproteins, growth factors, morphogens, and cytokines that are important regulators of regeneration. We also discuss the potential for syndecans to regulate stem cell properties, and suggest that understanding these proteoglycans is relevant to exploiting cell, tissue, and materials technologies.

show abstract

Emerging roles of syndecan 2 in epithelial and mesenchymal cancer progression

et al. 2017

View full text Add to dashboard Cite

Syndecan 2 (SDC2) belongs to a four-member family of evolutionary conserved small type I transmembrane proteoglycans consisting of a protein core to which glycosaminoglycan chains are covalently attached. SDC2 is a cell surface heparan sulfate proteoglycan, which is increasingly drawing attention for its distinct characteristics and its participation in numerous cell functions, including those related to carcinogenesis. Increasing evidence suggests that the role of SDC2 in cancer pathogenesis is dependent on cancer tissue origin rendering its use as a biomarker/therapeutic target feasible. This mini review discusses the mechanisms, through which SDC2, in a distinct manner, modulates complex signalling networks to affect cancer progression. © 2017 IUBMB Life, 69(11):824-833, 2017.

show abstract

Trans-regulation of Syndecan Functions by Hetero-oligomerization

Cited by 21 publications

References 29 publications

The Conserved Phenylalanine in the Transmembrane Domain Enhances Heteromeric Interactions of Syndecans

The Conserved Phenylalanine in the Transmembrane Domain Enhances Heteromeric Interactions of Syndecans

Minireview: Syndecans and their crucial roles during tissue regeneration

Emerging roles of syndecan 2 in epithelial and mesenchymal cancer progression

Contact Info

Product

Resources

About