Wnt5a Signaling Induces Proliferation and Survival of Endothelial Cells In Vitro and Expression of MMP-1 and Tie-2

Masckauchán, T. Néstor H.; Agalliu, Dritan; Vorontchikhina, Marina; Ahn, Audrey; Parmalee, Nancy L.; Li, Chi Ming; Khoo, Alan Soo Beng; Tycko, Benjamin; Brown, Anthony M.; Kitajewski, Jan

doi:10.1091/mbc.e06-04-0320

Cited by 197 publications

(178 citation statements)

References 36 publications

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“…To further investigate whether CD146 can activate non-canonical Wnt signalling JNK alone, the expression levels of Wnt5a and several Wnt receptors were examined by reverse transcriptase-PCR in HEK293T and HUVECs. Our results show that Wnt5a and Wnt receptors were expressed in those cells as reported [21][22][23] . Subsequently, specific siRNAs were employed to knock down the different Wnt receptors in HEK293T cells ( Supplementary Fig.…”

supporting

confidence: 86%

Wnt5a uses CD146 as a receptor to regulate cell motility and convergent extension

Zhang

et al. 2013

Nat Commun

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Dysregulation of Wnt signalling leads to developmental defects and diseases. Non-canonical Wnt signalling via planar cell polarity proteins regulates cell migration and convergent extension; however, the underlying mechanisms are poorly understood. Here we report that Wnt5a uses CD146 as a receptor to regulate cell migration and zebrafish embryonic convergent extension. CD146 binds to Wnt5a with the high affinity required for Wnt5a-induced activation of Dishevelled (Dvl) and c-jun amino-terminal kinase (JNK). The interaction between CD146 and Dvl2 is enhanced on Wnt5a treatment. Mutation of the Dvl2-binding region impairs its ability to activate JNK, promote cell migration and facilitate the formation of cell protrusions. Knockdown of Dvls impairs CD146-induced cell migration. Interestingly, CD146 inhibits canonical Wnt signalling by promoting b-catenin degradation.Our results suggest a model in which CD146 acts as a functional Wnt5a receptor in regulating cell migration and convergent extension, turning off the canonical Wnt signalling branch.

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supporting

confidence: 86%

Wnt5a uses CD146 as a receptor to regulate cell motility and convergent extension

Zhang

et al. 2013

Nat Commun

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“…It was also shown previously that Wnt5a induces the expression of MMP-1 in endothelial cells although the mechanism was not known (Masckauchan et al, 2006). This study found that Wnt5a induces the phosphorylation of PKD/ PKCm, which is a direct target of novel PKCs (PKCd, PKCe, PKCZ and PKCy), and activates JNK.…”

Section: Mechanism By Which Wnt5a Promotes Aggressiveness Of Pcasupporting

confidence: 53%

Wnt5a signaling is involved in the aggressiveness of prostate cancer and expression of metalloproteinase

et al. 2010

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Wnt5a is a representative ligand that activates the b-catenin-independent pathway in Wnt signaling. Although it has been reported that abnormal activation of the Wnt/ b-catenin-dependent pathway is often observed in human prostate cancer, the involvement of the b-catenin-independent pathway in this cancer is unclear. Abnormal expression of Wnt5a and b-catenin was observed in 27 (28%) and 49 (50%) of 98 prostate cancer cases, respectively, by immunohistochemical analyses. Simultaneous expression of Wnt5a and b-catenin was observed in only five cases, suggesting their exclusive expression. The positive detection of Wnt5a was correlated with high Gleason scores and biochemical relapse of prostate cancer, but that of b-catenin was not. Knockdown and overexpression of Wnt5a in human prostate cancer cell lines reduced and stimulated, respectively, their invasion activities, and the invasion activity required Frizzled2 and Ror2 as Wnt receptors. Wnt5a activated Jun-N-terminal kinase through protein kinase D (PKD) and the inhibition of PKD suppressed Wnt5a-dependent cell migration and invasion. In addition, Wnt5a induced the expression of metalloproteinase-1 through the recruitment of JunD to its promoter region. These results suggest that Wnt5a promotes the aggressiveness of prostate cancer and that its expression is involved in relapse after prostatectomy.

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“…The siRNA sequences used were: Ror2 siRNA #1, 5 0 -GCAA T G T GC T AG T G T ACGA TT-3 0 ; control siRNA #1, 5 0 -G T ACCGCACG T CA TT CG T A T C-3 0 (RNAi Co., Ltd, Tokyo, Japan); Ror2 siRNA #2, 5 0 -TAAAGGGTCGTTCGGATCCAGAACC-3 0 ; control siRNA #2, Medium GC Duplex 2 (Invitrogen); MMP-13 siRNA 5 0 -GATAACACCTTAGATGTCATT-3 0 (Sigma, St Louis, MO, USA). The Wnt5a siRNA was as described by Masckauchan et al (2006). An anti-Ror2 antibody was prepared as previously described by Kani et al (2004).…”

Section: Plasmids and Sirnasmentioning

confidence: 99%

“…It has been shown that Ror2 mediates Wnt5a signaling by activating the Wnt/JNK pathway and inhibiting the b-catenin-TCF pathway (Oishi et al, 2003;Mikels and Nusse, 2006). Studies using cultured mammalian cells show that Wnt5a promotes cell migration (Weeraratna et al, 2002;Kodama et al, 2004;Masckauchan et al, 2006), and that Ror2 mediates Wnt5a-induced cell migration through its association with the actin-binding protein, filamin A (Nishita et al, 2006). In addition, it has recently been reported that Wnt5a regulates cell polarity in cooperation with Par/Atypical protein kinase C pathway (Schlessinger et al, 2007), and that Ror2 mediates Wnt5a-induced polarized cell migration by activating JNK through its association with filamin A (Nomachi et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Autonomous regulation of osteosarcoma cell invasiveness by Wnt5a/Ror2 signaling

et al. 2009

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The receptor tyrosine kinase Ror2 regulates cell migration by acting as a receptor or co-receptor for Wnt5a. Although Wnt5a has been implicated in the invasiveness of several types of tumors, the role of Ror2 in tumor invasion remains elusive. Here we show that osteosarcoma cell lines SaOS-2 and U2OS show invasive properties in vitro by activating Wnt5a/Ror2 signaling in a cell-autonomous manner. The suppressed expression of either Wnt5a or Ror2 in osteosarcoma cells inhibits cell invasiveness accompanying decreased invadopodia formation. Gene-expression profiling identified matrix metalloproteinase 13 (MMP-13) as one of the genes whose expression is downregulated in SaOS-2 cells following suppression of Ror2 expression. Reduced expression or activity of MMP-13 suppresses invasiveness of SaOS-2 cells. Moreover, expression of MMP-13 and cell invasiveness by Wnt5a/Ror2 signaling can be abrogated by an inhibitor of the Src-family protein tyrosine kinases (SFKs), suggesting the role of the SFKs in MMP-13 expression through Wnt5a/Ror2 signaling. We further show that activation of an SFK is inhibited by the suppressed expression of Ror2. Collectively, these results indicate that Wnt5a/Ror2 signaling involves the activation of a SFK, leading to MMP-13 expression, and that constitutively active Wnt5a/Ror2 signaling confers invasive properties on osteosarcoma cells in a cell-autonomous manner.

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Wnt5a Signaling Induces Proliferation and Survival of Endothelial Cells In Vitro and Expression of MMP-1 and Tie-2

Cited by 197 publications

References 36 publications

Wnt5a uses CD146 as a receptor to regulate cell motility and convergent extension

Wnt5a uses CD146 as a receptor to regulate cell motility and convergent extension

Wnt5a signaling is involved in the aggressiveness of prostate cancer and expression of metalloproteinase

Autonomous regulation of osteosarcoma cell invasiveness by Wnt5a/Ror2 signaling

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