| pubmed-article:19556343 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:19556343 | lifeskim:mentions | umls-concept:C0682972 | lld:lifeskim |
| pubmed-article:19556343 | lifeskim:mentions | umls-concept:C0037083 | lld:lifeskim |
| pubmed-article:19556343 | lifeskim:mentions | umls-concept:C0031727 | lld:lifeskim |
| pubmed-article:19556343 | lifeskim:mentions | umls-concept:C0021467 | lld:lifeskim |
| pubmed-article:19556343 | lifeskim:mentions | umls-concept:C1366490 | lld:lifeskim |
| pubmed-article:19556343 | lifeskim:mentions | umls-concept:C1710082 | lld:lifeskim |
| pubmed-article:19556343 | lifeskim:mentions | umls-concept:C0021469 | lld:lifeskim |
| pubmed-article:19556343 | pubmed:issue | 9 | lld:pubmed |
| pubmed-article:19556343 | pubmed:dateCreated | 2009-8-28 | lld:pubmed |
| pubmed-article:19556343 | pubmed:abstractText | Activation of Wnt signaling pathways causes release and stabilization of the transcription regulator beta-catenin from a destruction complex composed of axin and the adenomatous polyposis coli (APC) protein (canonical signaling pathway). Assembly of this complex is facilitated by a protein-protein interaction between APC and a regulator of G protein signaling (RGS) domain in axin. Because G protein-coupled receptor kinase 2 (GRK2) has a RGS domain that is closely related to the RGS domain in axin, we determined whether GRK2 regulated canonical signaling. We found that GRK2 inhibited Wnt1-induced activation of a reporter construct as well as reduced Wnt3a-dependent stabilization and nuclear translocation of beta-catenin. GRK2 enzymatic activity was required for this negative regulatory effect, and depletion of endogenous GRK2 using small interfering RNA enhanced canonical signaling. GRK2-dependent inhibition of canonical signaling is relevant to osteoblast (OB) biology because overexpression of GRK2 attenuated Wnt/beta-catenin signaling in calvarial OBs. Coimmunoprecipitation studies found that: 1) GRK2 bound APC; 2) The GRK2-APC interaction was promoted by GRK2 enzymatic activity; and 3) Deletion of the RGS domain in GRK2 prevented both the GRK2-APC interaction and GRK2-dependent inhibition of canonical signaling. These data suggest that: 1) GRK2 negatively regulates Wnt signaling; 2) GRK2-dependent inhibition of canonical signaling requires a protein-protein interaction between the RGS domain in GRK2 and APC; and 3) Enzymatic activity promotes the GRK2-APC interaction and is required for the negative regulatory effect on canonical signaling. We speculate that inhibiting GRK2 activity in bone-forming OBs might be a useful therapeutic strategy for increasing bone mass. | lld:pubmed |
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| pubmed-article:19556343 | pubmed:grant | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:19556343 | pubmed:language | eng | lld:pubmed |
| pubmed-article:19556343 | pubmed:journal | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:19556343 | pubmed:citationSubset | IM | lld:pubmed |
| pubmed-article:19556343 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
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| pubmed-article:19556343 | pubmed:status | MEDLINE | lld:pubmed |
| pubmed-article:19556343 | pubmed:month | Sep | lld:pubmed |
| pubmed-article:19556343 | pubmed:issn | 1944-9917 | lld:pubmed |
| pubmed-article:19556343 | pubmed:author | pubmed-author:WangLimingL | lld:pubmed |
| pubmed-article:19556343 | pubmed:author | pubmed-author:SpurneyRobert... | lld:pubmed |
| pubmed-article:19556343 | pubmed:author | pubmed-author:FieldsTimothy... | lld:pubmed |
| pubmed-article:19556343 | pubmed:author | pubmed-author:Gesty-PalmerD... | lld:pubmed |
| pubmed-article:19556343 | pubmed:issnType | Electronic | lld:pubmed |
| pubmed-article:19556343 | pubmed:volume | 23 | lld:pubmed |
| pubmed-article:19556343 | pubmed:owner | NLM | lld:pubmed |
| pubmed-article:19556343 | pubmed:authorsComplete | Y | lld:pubmed |
| pubmed-article:19556343 | pubmed:pagination | 1455-65 | lld:pubmed |
| pubmed-article:19556343 | pubmed:dateRevised | 2010-9-2 | lld:pubmed |
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| pubmed-article:19556343 | pubmed:meshHeading | pubmed-meshheading:19556343... | lld:pubmed |
| pubmed-article:19556343 | pubmed:meshHeading | pubmed-meshheading:19556343... | lld:pubmed |
| pubmed-article:19556343 | pubmed:year | 2009 | lld:pubmed |
| pubmed-article:19556343 | pubmed:articleTitle | Inhibition of WNT signaling by G protein-coupled receptor (GPCR) kinase 2 (GRK2). | lld:pubmed |
| pubmed-article:19556343 | pubmed:affiliation | Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA. | lld:pubmed |
| pubmed-article:19556343 | pubmed:publicationType | Journal Article | lld:pubmed |
| pubmed-article:19556343 | pubmed:publicationType | Research Support, Non-U.S. Gov't | lld:pubmed |
| pubmed-article:19556343 | pubmed:publicationType | Research Support, N.I.H., Extramural | lld:pubmed |
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