Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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CSK Tyrosine-Protein Kinase
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Cell Line, Tumor
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Cell Movement / genetics
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Cell Movement / physiology*
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Enzyme Activation / drug effects
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Extracellular Matrix / metabolism
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Gene Expression Regulation, Neoplastic
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / metabolism
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Humans
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Immunoblotting
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Matrix Metalloproteinase 13 / genetics
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Matrix Metalloproteinase 13 / metabolism
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Microscopy, Fluorescence
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Neoplasm Invasiveness
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Oligonucleotide Array Sequence Analysis
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Osteosarcoma / genetics
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Osteosarcoma / metabolism
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Osteosarcoma / pathology
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Pyrimidines / pharmacology
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RNA, Small Interfering / genetics
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Receptor Tyrosine Kinase-like Orphan Receptors
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / metabolism*
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / genetics
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Signal Transduction / physiology*
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Transfection
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Wnt Proteins / genetics
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Wnt Proteins / metabolism*
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Wnt-5a Protein
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src-Family Kinases
Substances
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AG 1879
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Proto-Oncogene Proteins
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Pyrimidines
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RNA, Small Interfering
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Receptors, Cell Surface
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Recombinant Fusion Proteins
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WNT5A protein, human
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Wnt Proteins
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Wnt-5a Protein
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Green Fluorescent Proteins
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Protein-Tyrosine Kinases
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ROR2 protein, human
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Receptor Tyrosine Kinase-like Orphan Receptors
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CSK Tyrosine-Protein Kinase
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src-Family Kinases
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CSK protein, human
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Matrix Metalloproteinase 13