Regulation of Wnt5a expression in human mammary cells by protein kinase C activity and the cytoskeleton

Jönsson, Mats; Smith, Kelly J.; Harris, Adrian L.

doi:10.1038/bjc.1998.511

Cited by 40 publications

(27 citation statements)

References 32 publications

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“…3). Not only can Wnt5A activate PKC, but PKC activation has been shown to activate Wnt5A in a positive feedback loop in breast cancer cells (31). We found this to be true also for our melanoma cells after 24 h of continued phorbol ester treatment (Fig.…”

Section: Resultssupporting

confidence: 72%

The Wnt5A/Protein Kinase C Pathway Mediates Motility in Melanoma Cells via the Inhibition of Metastasis Suppressors and Initiation of an Epithelial to Mesenchymal Transition

Dissanayake

Wade

Johnson

et al. 2007

Journal of Biological Chemistry

338

363

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We have shown that Wnt5A increases the motility of melanoma cells. To explore cellular pathways involving Wnt5A, we compared gain-of-function (WNT5A stable transfectants) versus loss-of-function (siRNA knockdown) of WNT5A by microarray analysis. Increasing WNT5A suppressed the expression of several genes, which were re-expressed after small interference RNA-mediated knockdown of WNT5A. Genes affected by WNT5A include KISS-1, a metastasis suppressor, and CD44, involved in tumor cell homing during metastasis. This could be validated at the protein level using both small interference RNA and recombinant Wnt5A (rWnt5A). Among the genes up-regulated by WNT5A was the gene vimentin, associated with an epithelial to mesenchymal transition (EMT), which involves decreases in E-cadherin, due to up-regulation of the transcriptional repressor, Snail. rWnt5A treatment increases Snail and vimentin expression, and decreases E-cadherin, even in the presence of dominant-negativeTCF4, suggesting that this activation is independent of Wnt/␤-catenin signaling. Because Wnt5A can signal via protein kinase C (PKC), the role of PKC in Wnt5A-mediated motility and EMT was also assessed using PKC inhibition and activation studies. Treating cells expressing low levels of Wnt5A with phorbol ester increased Snail expression inhibiting PKC in cells expressing high levels of Wnt5A decreased Snail. Furthermore, inhibition of PKC before Wnt5A treatment blocked Snail expression, implying that Wnt5A can potentiate melanoma metastasis via the induction of EMT in a PKC-dependent manner.The molecular mechanisms that govern the motility and metastasis of melanoma cells are not well understood. The prognosis for patients with recurrent melanoma has shown no improvement over the past 50 years. Many of these tumors are histopathologically quite similar but can be subclassified based upon their gene expression profiles (1, 2). In a study by Bittner et al. (1), the gene that best separated highly aggressive tumors from less aggressive tumors was WNT5A, which was consistently underexpressed in the less motile tumors. Wnt5A is a member of the Wnt family of proteins, which were first identified during studies of development in Drosophila (3) and in studies of the mouse mammary tumor virus (4). Unlike its family members Wnt1 and Wnt3A, which signal via the canonical Wnt pathway, resulting in the nuclear translocation of ␤-catenin, Wnt5A acts via G-protein-coupled receptors to activate protein kinase C (PKC) 6 and intracellular calcium (5, 6). The interplay between these two pathways is not well understood, but it does appear that the non-canonical Wnt pathway can inhibit ␤-catenin stabilization both in vitro in human HEK293 cells and in vivo in zebrafish (7,8).In melanoma cells with low motility and low expression of WNT5A, overexpressing WNT5A resulted in an increase in both the activation of PKC and an increase in motility (9). High expression of WNT5A in melanoma patients also correlated to poor outcome in this study. In addition, many studies have highligh...

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Section: Resultssupporting

confidence: 72%

The Wnt5A/Protein Kinase C Pathway Mediates Motility in Melanoma Cells via the Inhibition of Metastasis Suppressors and Initiation of an Epithelial to Mesenchymal Transition

Dissanayake

Wade

Johnson

et al. 2007

Journal of Biological Chemistry

338

363

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“…PKC up-regulation has been shown to stabilize Wnt5A mRNA, thereby increasing Wnt5A levels (37). Changes induced by Wnt5A activation of Ca 2ϩ /PKC include down-regulation of the metastasis suppressor Kiss-1 and up-regulation of CD44, Snail, and vimentin, leading to an epithelial to mesenchymal transition (2).…”

Section: Discussionmentioning

confidence: 99%

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

O’Connell

Fiori

Kershner

et al. 2009

Journal of Biological Chemistry

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Heparan sulfate proteoglycans (HSPGs) are important modulators for optimizing signal transduction of many pathways, including the Wnt pathways. We demonstrate that HSPG glycosaminoglycan levels increased with increasing metastatic potential of melanoma cells. Previous studies have demonstrated that Wnt5A increases the invasiveness of melanoma cells. We further demonstrate that HSPGs potentiate Wnt5A signaling, since enzymatic removal of the HSPG backbone resulted in a decrease in cellular Wnt5A levels, an increase in secreted Wnt5A in cell media, a decrease in downstream signaling, and ultimately, a decrease in invasiveness. Specifically, syndecan 1 and syndecan 4 expression correlated to Wnt5A expression and melanoma malignancy. Knockdown of syndecan 1 or 4 caused decreases in cell invasion, which could be restored by treating the cells with recombinant Wnt5A. These data indicate that syndecan 1 and 4 correlate to increased metastatic potential in melanoma patients and are an important component of the Wnt5A autocrine signaling loop, the activation of which leads to increased metastasis of melanoma.

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“…11), a membrane-associated protein that mediates intercellular adhesion in intestinal epithelial cells (81). It is of interest to note that previous studies have shown that cytoskeletal rearrangement can stimulate expression of Wnt5a (82), but the reverse has not been established. We also show that Wnt11 causes increased cell migration as demonstrated by a wound-healing scratch assay (Fig.…”

Section: Discussionmentioning

confidence: 99%

Wnt11 Signaling Promotes Proliferation, Transformation, and Migration of IEC6 Intestinal Epithelial Cells

Ouko

Ziegler

et al. 2004

Journal of Biological Chemistry

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Regulation of Wnt5a expression in human mammary cells by protein kinase C activity and the cytoskeleton

Cited by 40 publications

References 32 publications

The Wnt5A/Protein Kinase C Pathway Mediates Motility in Melanoma Cells via the Inhibition of Metastasis Suppressors and Initiation of an Epithelial to Mesenchymal Transition

The Wnt5A/Protein Kinase C Pathway Mediates Motility in Melanoma Cells via the Inhibition of Metastasis Suppressors and Initiation of an Epithelial to Mesenchymal Transition

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

Wnt11 Signaling Promotes Proliferation, Transformation, and Migration of IEC6 Intestinal Epithelial Cells

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