Heparan Sulfate Proteoglycan Modulation of Wnt5A Signal Transduction in Metastatic Melanoma Cells

O’Connell, Michael P.; Fiori, Jennifer L.; Kershner, Emily; Frank, Brittany P.; Indig, Fred E.; Taub, Dennis D.; Hoek, Keith S.; Weeraratna, Ashani T.

doi:10.1074/jbc.m109.028498

Cited by 71 publications

(70 citation statements)

References 48 publications

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“…It has also been shown that GPCs and SDCs affect distinct intracellular pathways of Wnt signaling (Alexander et al, 2000;Capurro et al, 2005a;De Cat et al, 2003;Munoz et al, 2006;O'Connell et al, 2009;Ohkawara et al, 2003). In this study, we demonstrated that GPC4 activates both the b-catenin-dependent and -independent pathway of Wnt signaling and that GPC4 ectodomain released from the cell surface membrane inhibits Wnt signaling.…”

Section: Discussionmentioning

confidence: 50%

“…SDC4 has been shown to bind to Fz7 and Dvl and to be required for convergent extension in Xenopus (Munoz et al, 2006). Expression of SDC1 and SDC4 correlates with Wnt5a expression in melanoma cell lines, and knockdown of SDC1 and SDC4 decreases cell invasion activity, which is restored by Wnt5a (O'Connell et al, 2009). Thus, whether the action of HSPG is positive or negative for the b-catenin-dependent or -independent pathway might in part be dependent on the type of cell or tissue.…”

Section: Introductionmentioning

confidence: 99%

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Localization of glypican-4 in different membrane microdomains is involved in the regulation of Wnt signaling

Sakane

Yamamoto

Matsumoto

et al. 2012

Journal of Cell Science

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SummaryGlypicans are members of the heparan sulfate proteoglycans (HSPGs) and are involved in various growth factor signaling mechanisms. Although HSPGs affect the b-catenin-dependent and -independent pathways of Wnt signaling, how they regulate distinct Wnt pathways is not clear. It has been suggested that the b-catenin-dependent pathway is initiated through receptor endocytosis in lipid raft microdomains and the independent pathway is activated through receptor endocytosis in non-lipid raft microdomains. Here, evidence is presented that glypican-4 (GPC4) is localized to both membrane microdomains and that the localization affects its ability to regulate distinct Wnt pathways. GPC4 bound to Wnt3a and Wnt5a, which activate the b-catenin-dependent and -independent pathways, respectively, and colocalized with Wnts on the cell surface. LRP6, one of Wnt3a coreceptors, was present in lipid raft microdomains, whereas Ror2, one of Wnt5a coreceptors, was localized to non-lipid raft microdomains. Expression of GPC4 enhanced the Wnt3a-dependent b-catenin pathway and the Wnt5a-dependent b-catenin-independent pathway, and knockdown of GPC4 suppressed both pathways. A GPC4 mutant that was localized to only non-lipid raft microdomains inhibited the b-catenin-dependent pathway but enhanced the b-catenin-independent pathway. These results suggest that GPC4 concentrates Wnt3a and Wnt5a to the vicinity of their specific receptors in different membrane microdomains, thereby regulating distinct Wnt signaling.

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Section: Discussionmentioning

confidence: 50%

Section: Introductionmentioning

confidence: 99%

Localization of glypican-4 in different membrane microdomains is involved in the regulation of Wnt signaling

Sakane

Yamamoto

Matsumoto

et al. 2012

Journal of Cell Science

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“…SDC4 overexpression or knockout compromises cell migration in normal (5) and tumorigenic cells (6). More recently it was demonstrated that SDC4 is required for localization of Rac1 and membrane protrusion formation at the leading edge to allow celldirected migration (7).…”

mentioning

confidence: 99%

Non-canonical Wnt Signaling Induces Ubiquitination and Degradation of Syndecan4

Carvallo¹,

Muñoz²,

Bustos

et al. 2010

Journal of Biological Chemistry

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Dynamic regulation of cell adhesion receptors is required for proper cell migration in embryogenesis, tissue repair, and cancer. Integrins and Syndecan4 (SDC4) are the main cell adhesion receptors involved in focal adhesion formation and are required for cell migration. SDC4 interacts biochemically and functionally with components of the Wnt pathway such as Frizzled7 and Dishevelled. Non-canonical Wnt signaling, particularly components of the planar cell polarity branch, controls cell adhesion and migration in embryogenesis and metastasic events. Here, we evaluate the effect of this pathway on SDC4. We have found that Wnt5a reduces cell surface levels and promotes ubiquitination and degradation of SDC4 in cell lines and dorsal mesodermal cells from Xenopus gastrulae. Gain-and loss-of-function experiments demonstrate that Dsh plays a key role in regulating SDC4 steady-state levels. Moreover, a SDC4 deletion construct that interacts inefficiently with Dsh is resistant to Wnt5a-induced degradation. Non-canonical Wnt signaling promotes monoubiquitination of the variable region of SDC4 cytoplasmic domain. Mutation of these specific residues abrogates ubiquitination and results in increased SDC4 steadystate levels. This is the first example of a cell surface protein ubiquitinated and degraded in a Wnt/Dsh-dependent manner.Cell adhesion and migration are key processes for embryogenesis, inflammatory response, tissue repair, and cancer. Cell migration is a very dynamic process that requires the continuous assembly and disassembly of the cell surface complexes mediating cell-cell and cell-extracellular matrix adhesion (1, 2). Integrins and Syndecans are the main cell adhesion receptors involved in focal adhesion (FA) 5 formation and cell-extracellular matrix communication (3). FA formation of cells plated on fibronectin requires the specific engagement and synergism between ␣5␤1 integrin and Syndecan4 (SDC4)(3, 4).SDC4 is a cell surface heparan sulfate proteoglycan that activates intracellular signaling cascades through activation of PKC␣ (4). SDC4 overexpression or knockout compromises cell migration in normal (5) and tumorigenic cells (6). More recently it was demonstrated that SDC4 is required for localization of Rac1 and membrane protrusion formation at the leading edge to allow celldirected migration (7). In normal and tumorigenic cells, endocytosis and recycling of integrins modulate FA turnover and proper cell migration (8, 9). Which extracellular cues regulate the stability and turnover of FA receptors, in particular of SDC4, is a key question to understand cell migration.Wnt proteins constitute a large family of secreted glycoproteins that can activate diverse intracellular signaling pathways in a context-dependent manner. Wnt5a is known to promote polarized cell migration by activating a non-canonical Wnt pathway through the tyrosine kinase Ror2 receptor and c-Jun N-terminal kinase (10 -12). Wnt5a increases cell migration and invasiveness of tumorigenic cells by activation of FA kinase, PKC, Rac1, and promoti...

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“…Syndecans play important roles in different physiological functions, including embryo development, vasculation, neural migration, signaling, inflammation, angiogenesis, and focal adhesion (3)(4)(5)(6)(7). There are four members of the syndecan family in vertebrates, as follows: syndecan-1, -2, -3, and -4.…”

mentioning

confidence: 99%

Removal of Syndecan-1 Promotes TRAIL-Induced Apoptosis in Myeloma Cells

Wu¹,

Yang

Chien

et al. 2012

The Journal of Immunology

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Syndecan is the major transmembrane proteoglycan in cells. Of the four syndecans, syndecan-1 is the dominant form expressed in multiple myeloma and is an indicator of poor prognosis. In the current study, we observed that early TRAIL-induced apoptotic processes were accompanied by cleavage of syndecan-1 intracellular region, and explored the possibility whether removal of syndecan-1 promotes apoptotic processes. We found that syndecan-1 knockdown by specific small interfering RNA in multiple myeloma enhanced TRAIL-induced apoptosis, even though the expression of TRAIL receptors and several apoptosis-associated molecules was unaffected. The enhanced TRAIL-mediated apoptosis in syndecan-1–deficient cells was not due to a decrease in surface heparan sulfate or a reduction in TRAIL receptor endocytosis. The increase in TRAIL-induced cell death was accompanied by an elevated caspase-8 activation and an enhanced formation of death-inducing signaling complexes, which could be attributed to an increased expression of TRAIL receptor O-glycosylation enzyme in syndecan-1–deficient cells. We also found that in H9 lymphoma and Jurkat cells, knockdown of the predominant syndecan member also led to an increase in Fas ligand-induced apoptosis. Our results demonstrate that syndecan plays a negative role in death receptor-mediated cell death, suggesting potential application of syndecan downregulation in the treatment of myeloma in combination with TRAIL.

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Heparan Sulfate Proteoglycan Modulation of Wnt5A Signal Transduction in Metastatic Melanoma Cells

Cited by 71 publications

References 48 publications

Localization of glypican-4 in different membrane microdomains is involved in the regulation of Wnt signaling

Localization of glypican-4 in different membrane microdomains is involved in the regulation of Wnt signaling

Non-canonical Wnt Signaling Induces Ubiquitination and Degradation of Syndecan4

Removal of Syndecan-1 Promotes TRAIL-Induced Apoptosis in Myeloma Cells

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