Wnt5a regulates distinct signalling pathways by binding to Frizzled2
Wnt5a regulates multiple intracellular signalling cascades, but how Wnt5a determines the specificity of these pathways is not well understood. This study examined whether the internalization of Wnt receptors affects the ability of Wnt5a to regulate its signalling pathways. Wnt5a activated Rac in the...
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| Veröffentlicht in: | The EMBO journal 2010-01, Vol.29 (1), p.41-54 |
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| creator | Sato, Akira Yamamoto, Hideki Sakane, Hiroshi Koyama, Hirofumi Kikuchi, Akira |
| description | Wnt5a regulates multiple intracellular signalling cascades, but how Wnt5a determines the specificity of these pathways is not well understood. This study examined whether the internalization of Wnt receptors affects the ability of Wnt5a to regulate its signalling pathways. Wnt5a activated Rac in the β‐catenin‐independent pathway, and Frizzled2 (Fz2) and Ror1 or Ror2 were required for this action. Fz2 was internalized through a clathrin‐mediated route in response to Wnt5a, and inhibition of clathrin‐dependent internalization suppressed the ability of Wnt5a to activate Rac. As another action of Wnt5a, it inhibited Wnt3a‐dependent lipoprotein receptor‐related protein 6 (LRP6) phosphorylation and β‐catenin accumulation. Wnt3a‐dependent phosphorylation of LRP6 was enhanced in Wnt5a knockout embryonic fibroblasts. Fz2 was also required for the Wnt3a‐dependent accumulation of β‐catenin, and Wnt5a competed with Wnt3a for binding to Fz2
in vitro
and in intact cells, thereby inhibiting the β‐catenin pathway. This inhibitory action of Wnt5a was not affected by the impairment of clathrin‐dependent internalization. These results suggest that Wnt5a regulates distinct pathways through receptor internalization‐dependent and ‐independent mechanisms. |
| doi_str_mv | 10.1038/emboj.2009.322 |
| format | Article |
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in vitro
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in vitro
and in intact cells, thereby inhibiting the β‐catenin pathway. This inhibitory action of Wnt5a was not affected by the impairment of clathrin‐dependent internalization. These results suggest that Wnt5a regulates distinct pathways through receptor internalization‐dependent and ‐independent mechanisms.</description><subject>Accumulation</subject><subject>Animals</subject><subject>beta Catenin - metabolism</subject><subject>Binding sites</subject><subject>Binding, Competitive</subject><subject>Cell Line</subject><subject>Cellular biology</subject><subject>CHO Cells</subject><subject>Clathrin - metabolism</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>EMBO20</subject><subject>EMBO37</subject><subject>endocytosis</subject><subject>Frizzled Receptors - metabolism</subject><subject>Frizzled2</subject><subject>HeLa Cells</subject><subject>Humans</subject><subject>L Cells (Cell Line)</subject><subject>LDL-Receptor Related Proteins - metabolism</subject><subject>Low Density Lipoprotein Receptor-Related Protein-6</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Molecular biology</subject><subject>Phosphorylation</subject><subject>Protein Binding</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins - genetics</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Proto-Oncogene Proteins - pharmacology</subject><subject>Rac</subject><subject>rac GTP-Binding Proteins - metabolism</subject><subject>Receptors, G-Protein-Coupled - metabolism</subject><subject>Recombinant Proteins - genetics</subject><subject>Recombinant Proteins - metabolism</subject><subject>RNA, Small Interfering - genetics</subject><subject>Signal Transduction</subject><subject>Wnt Proteins - antagonists & inhibitors</subject><subject>Wnt Proteins - deficiency</subject><subject>Wnt Proteins - genetics</subject><subject>Wnt Proteins - metabolism</subject><subject>Wnt Proteins - pharmacology</subject><subject>Wnt-5a Protein</subject><subject>Wnt3 Protein</subject><subject>Wnt3A Protein</subject><subject>Wnt5a</subject><subject>β-catenin</subject><issn>0261-4189</issn><issn>1460-2075</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqFkt1v0zAUxS3ExMrglUcU8cJTOn_EdvyCxMbWMWUgJNAeLSe56VxSp9gJo_vrcZaqG0gIyZJl-3ePz_UxQq8InhPM8mNYl91qTjFWc0bpEzQjmcApxZI_RTNMBUkzkqtD9DyEFcaY55I8Q4dEKYIVZTP04dr13CQelkNreghJbUNvXdUnwS6daVvrlsnG9De3ZhuScpuU1tXjXt8l597e3bVQ0xfooDFtgJe7-Qh9Oz_7enqRFp8XH0_fF2nFhaIpyUouedZUrFYcgOI4FBVQi5wAZoJmpaKcYclyrDgVTSlqSmSTcd40oDJ2hN5NupuhXENdgeu9afXG27XxW90Zq_88cfZGL7ufmuY4ZxJHgbc7Ad_9GCD0em1DBW1rHHRD0JJllFKGSSTf_EWuusHHBwmajN4oy0WE5hNU-S4ED83eCsF6jEffx6PHeHSMJxa8ftzAA77LIwJyAm5tC9v_yOmzq5PLcTFJH0-VIRa5JfhHhv9lZteiM_3gYX_ZPfYgm05Q_Bbwa88Y_10LySTX158W-uKKFYsvJ4Uu2G_6scbL</recordid><startdate>20100106</startdate><enddate>20100106</enddate><creator>Sato, Akira</creator><creator>Yamamoto, Hideki</creator><creator>Sakane, Hiroshi</creator><creator>Koyama, Hirofumi</creator><creator>Kikuchi, Akira</creator><general>John Wiley & Sons, Ltd</general><general>Nature Publishing Group UK</general><general>Blackwell Publishing Ltd</general><general>Nature Publishing Group</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>BKSAR</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7N</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PCBAR</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20100106</creationdate><title>Wnt5a regulates distinct signalling pathways by binding to Frizzled2</title><author>Sato, Akira ; Yamamoto, Hideki ; Sakane, Hiroshi ; Koyama, Hirofumi ; Kikuchi, Akira</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5692-14b5754fc3d95ee20e20926ed681e03624b9253073809526fb6d217f455ffe943</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Accumulation</topic><topic>Animals</topic><topic>beta Catenin - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The EMBO journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>Sato, Akira</au><au>Yamamoto, Hideki</au><au>Sakane, Hiroshi</au><au>Koyama, Hirofumi</au><au>Kikuchi, Akira</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Wnt5a regulates distinct signalling pathways by binding to Frizzled2</atitle><jtitle>The EMBO journal</jtitle><stitle>EMBO J</stitle><addtitle>EMBO J</addtitle><date>2010-01-06</date><risdate>2010</risdate><volume>29</volume><issue>1</issue><spage>41</spage><epage>54</epage><pages>41-54</pages><issn>0261-4189</issn><eissn>1460-2075</eissn><coden>EMJODG</coden><abstract>Wnt5a regulates multiple intracellular signalling cascades, but how Wnt5a determines the specificity of these pathways is not well understood. This study examined whether the internalization of Wnt receptors affects the ability of Wnt5a to regulate its signalling pathways. Wnt5a activated Rac in the β‐catenin‐independent pathway, and Frizzled2 (Fz2) and Ror1 or Ror2 were required for this action. Fz2 was internalized through a clathrin‐mediated route in response to Wnt5a, and inhibition of clathrin‐dependent internalization suppressed the ability of Wnt5a to activate Rac. As another action of Wnt5a, it inhibited Wnt3a‐dependent lipoprotein receptor‐related protein 6 (LRP6) phosphorylation and β‐catenin accumulation. Wnt3a‐dependent phosphorylation of LRP6 was enhanced in Wnt5a knockout embryonic fibroblasts. Fz2 was also required for the Wnt3a‐dependent accumulation of β‐catenin, and Wnt5a competed with Wnt3a for binding to Fz2
in vitro
and in intact cells, thereby inhibiting the β‐catenin pathway. This inhibitory action of Wnt5a was not affected by the impairment of clathrin‐dependent internalization. These results suggest that Wnt5a regulates distinct pathways through receptor internalization‐dependent and ‐independent mechanisms.</abstract><cop>Chichester, UK</cop><pub>John Wiley & Sons, Ltd</pub><pmid>19910923</pmid><doi>10.1038/emboj.2009.322</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Accumulation Animals beta Catenin - metabolism Binding sites Binding, Competitive Cell Line Cellular biology CHO Cells Clathrin - metabolism Cricetinae Cricetulus EMBO20 EMBO37 endocytosis Frizzled Receptors - metabolism Frizzled2 HeLa Cells Humans L Cells (Cell Line) LDL-Receptor Related Proteins - metabolism Low Density Lipoprotein Receptor-Related Protein-6 Mice Mice, Inbred C57BL Mice, Knockout Molecular biology Phosphorylation Protein Binding Proteins Proto-Oncogene Proteins - antagonists & inhibitors Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins - pharmacology Rac rac GTP-Binding Proteins - metabolism Receptors, G-Protein-Coupled - metabolism Recombinant Proteins - genetics Recombinant Proteins - metabolism RNA, Small Interfering - genetics Signal Transduction Wnt Proteins - antagonists & inhibitors Wnt Proteins - deficiency Wnt Proteins - genetics Wnt Proteins - metabolism Wnt Proteins - pharmacology Wnt-5a Protein Wnt3 Protein Wnt3A Protein Wnt5a β-catenin |
| title | Wnt5a regulates distinct signalling pathways by binding to Frizzled2 |
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