Integration of the beta-catenin-dependent Wnt pathway with integrin signaling through the adaptor molecule Grb2.
THE COMPLEXITY OF WNT SIGNALING LIKELY STEMS FROM TWO SOURCES: multiple pathways emanating from frizzled receptors in response to wnt binding, and modulation of those pathways and target gene responsiveness by context-dependent signals downstream of growth factor and matrix receptors. Both rac1 and...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2009-11-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC2773007?pdf=render |
| _version_ | 1818282371559981056 |
|---|---|
| author | Steve P Crampton Beibei Wu Edward J Park Jai-Hyun Kim Candice Solomon Marian L Waterman Christopher C W Hughes |
| author_facet | Steve P Crampton Beibei Wu Edward J Park Jai-Hyun Kim Candice Solomon Marian L Waterman Christopher C W Hughes |
| author_sort | Steve P Crampton |
| collection | DOAJ |
| description | THE COMPLEXITY OF WNT SIGNALING LIKELY STEMS FROM TWO SOURCES: multiple pathways emanating from frizzled receptors in response to wnt binding, and modulation of those pathways and target gene responsiveness by context-dependent signals downstream of growth factor and matrix receptors. Both rac1 and c-jun have recently been implicated in wnt signaling, however their upstream activators have not been identified.Here we identify the adapter protein Grb2, which is itself an integrator of multiple signaling pathways, as a modifier of beta-catenin-dependent wnt signaling. Grb2 synergizes with wnt3A, constitutively active (CA) LRP6, Dvl2 or CA-beta-catenin to drive a LEF/TCF-responsive reporter, and dominant negative (DN) Grb2 or siRNA to Grb2 block wnt3A-mediated reporter activity. MMP9 is a target of beta-catenin-dependent wnt signaling, and an MMP9 promoter reporter is also responsive to signals downstream of Grb2. Both a jnk inhibitor and DN-c-jun block transcriptional activation downstream of Dvl2 and Grb2, as does DN-rac1. Integrin ligation by collagen also synergizes with wnt signaling as does overexpression of Focal Adhesion Kinase (FAK), and this is blocked by DN-Grb2.These data suggest that integrin ligation and FAK activation synergize with wnt signaling through a Grb2-rac-jnk-c-jun pathway, providing a context-dependent mechanism for modulation of wnt signaling. |
| first_indexed | 2024-12-13T00:19:57Z |
| format | Article |
| id | doaj.art-8caafeacfa914d7ba703151ced3b9d45 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-13T00:19:57Z |
| publishDate | 2009-11-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-8caafeacfa914d7ba703151ced3b9d452022-12-22T00:05:39ZengPublic Library of Science (PLoS)PLoS ONE1932-62032009-11-01411e784110.1371/journal.pone.0007841Integration of the beta-catenin-dependent Wnt pathway with integrin signaling through the adaptor molecule Grb2.Steve P CramptonBeibei WuEdward J ParkJai-Hyun KimCandice SolomonMarian L WatermanChristopher C W HughesTHE COMPLEXITY OF WNT SIGNALING LIKELY STEMS FROM TWO SOURCES: multiple pathways emanating from frizzled receptors in response to wnt binding, and modulation of those pathways and target gene responsiveness by context-dependent signals downstream of growth factor and matrix receptors. Both rac1 and c-jun have recently been implicated in wnt signaling, however their upstream activators have not been identified.Here we identify the adapter protein Grb2, which is itself an integrator of multiple signaling pathways, as a modifier of beta-catenin-dependent wnt signaling. Grb2 synergizes with wnt3A, constitutively active (CA) LRP6, Dvl2 or CA-beta-catenin to drive a LEF/TCF-responsive reporter, and dominant negative (DN) Grb2 or siRNA to Grb2 block wnt3A-mediated reporter activity. MMP9 is a target of beta-catenin-dependent wnt signaling, and an MMP9 promoter reporter is also responsive to signals downstream of Grb2. Both a jnk inhibitor and DN-c-jun block transcriptional activation downstream of Dvl2 and Grb2, as does DN-rac1. Integrin ligation by collagen also synergizes with wnt signaling as does overexpression of Focal Adhesion Kinase (FAK), and this is blocked by DN-Grb2.These data suggest that integrin ligation and FAK activation synergize with wnt signaling through a Grb2-rac-jnk-c-jun pathway, providing a context-dependent mechanism for modulation of wnt signaling.http://europepmc.org/articles/PMC2773007?pdf=render |
| spellingShingle | Steve P Crampton Beibei Wu Edward J Park Jai-Hyun Kim Candice Solomon Marian L Waterman Christopher C W Hughes Integration of the beta-catenin-dependent Wnt pathway with integrin signaling through the adaptor molecule Grb2. PLoS ONE |
| title | Integration of the beta-catenin-dependent Wnt pathway with integrin signaling through the adaptor molecule Grb2. |
| title_full | Integration of the beta-catenin-dependent Wnt pathway with integrin signaling through the adaptor molecule Grb2. |
| title_fullStr | Integration of the beta-catenin-dependent Wnt pathway with integrin signaling through the adaptor molecule Grb2. |
| title_full_unstemmed | Integration of the beta-catenin-dependent Wnt pathway with integrin signaling through the adaptor molecule Grb2. |
| title_short | Integration of the beta-catenin-dependent Wnt pathway with integrin signaling through the adaptor molecule Grb2. |
| title_sort | integration of the beta catenin dependent wnt pathway with integrin signaling through the adaptor molecule grb2 |
| url | http://europepmc.org/articles/PMC2773007?pdf=render |
| work_keys_str_mv | AT stevepcrampton integrationofthebetacatenindependentwntpathwaywithintegrinsignalingthroughtheadaptormoleculegrb2 AT beibeiwu integrationofthebetacatenindependentwntpathwaywithintegrinsignalingthroughtheadaptormoleculegrb2 AT edwardjpark integrationofthebetacatenindependentwntpathwaywithintegrinsignalingthroughtheadaptormoleculegrb2 AT jaihyunkim integrationofthebetacatenindependentwntpathwaywithintegrinsignalingthroughtheadaptormoleculegrb2 AT candicesolomon integrationofthebetacatenindependentwntpathwaywithintegrinsignalingthroughtheadaptormoleculegrb2 AT marianlwaterman integrationofthebetacatenindependentwntpathwaywithintegrinsignalingthroughtheadaptormoleculegrb2 AT christophercwhughes integrationofthebetacatenindependentwntpathwaywithintegrinsignalingthroughtheadaptormoleculegrb2 |