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Wnt-5a-induced Phos...
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Hansen, ChristianLund University,Lunds universitet,Molekylär neurobiologi,Forskargrupper vid Lunds universitet,Experimentell patologi, Malmö,Molecular Neurobiology,Lund University Research Groups,Experimental Pathology, Malmö
(author)
Wnt-5a-induced Phosphorylation of DARPP-32 Inhibits Breast Cancer Cell Migration in a CREB-dependent Manner
- Article/chapterEnglish2009
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LIBRIS-ID:oai:DiVA.org:uu-127501
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-127501URI
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https://doi.org/10.1074/jbc.M109.048884DOI
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https://lup.lub.lu.se/record/1470124URI
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
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Tumor cell migration plays a central role in the process of cancer metastasis. We recently identified dopamine and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) as an antimigratory phosphoprotein in breast cancer cells. Here we link this effect of DARPP-32 to Wnt-5a signaling by demonstrating that recombinant Wnt-5a triggers cAMP elevation at the plasma membrane and Thr34-DARPP-32 phosphorylation in MCF-7 cells. In agreement, both protein kinase A (PKA) inhibitors and siRNA-mediated knockdown of Frizzled-3 receptor or G alpha(s) expression abolished Wnt-5a-induced phosphorylation of DARPP-32. Furthermore, Wnt-5a induced DARPP-32-dependent inhibition of MCF-7 cell migration. Phospho-Thr-34-DARPP-32 interacted with protein phosphatase-1 (PP1) and potentiated the Wnt-5a-mediated phosphorylation of CREB, a well-known PP1 substrate, but had no effect on CREB phosphorylation by itself. Moreover, inhibition of the Wnt-5a/DARPP-32/CREB pathway, by expression of dominant negative CREB (DN-CREB), diminished the antimigratory effect of Wnt-5a-induced phospho-Thr-34-DARPP-32. Phalloidin-staining revealed that that the presence of phospho-Thr-34-DARPP-32 in MCF-7 cells results in reduced filopodia formation. In accordance, the activity of the Rho GTPase Cdc42, known to be crucial for filopodia formation, was reduced in MCF-7 cells expressing phospho-Thr-34-DARPP- 32. The effects of DARPP-32 on cell migration and filopodia formation could be reversed in T47D breast cancer cells that were depleted of their endogenous DARPP-32 by siRNA targeting. Consequently, Wnt-5a activates a Frizzled-3/G alpha(s)/cAMP/PKA signaling pathway that triggers a DARPP-32- and CREB-dependent antimigratory response in breast cancer cells, representing a novel mechanism whereby Wnt-5a can inhibit breast cancer cell migration.
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Howlin, JillianLund University,Lunds universitet,Experimentell patologi, Malmö,Forskargrupper vid Lunds universitet,Experimental Pathology, Malmö,Lund University Research Groups(Swepub:lu)med-jho
(author)
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Tengholm, AndersUppsala universitet,Institutionen för medicinsk cellbiologi(Swepub:uu)andeteng
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Dyachok, OlegUppsala universitet,Institutionen för medicinsk cellbiologi(Swepub:uu)olegdyac
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Vogel, Wolfgang F.
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Nairn, Angus C.
(author)
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Greengard, Paul
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Andersson, TommyLund University,Lunds universitet,Experimentell patologi, Malmö,Forskargrupper vid Lunds universitet,Experimental Pathology, Malmö,Lund University Research Groups(Swepub:lu)expp-tan
(author)
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Molekylär neurobiologiForskargrupper vid Lunds universitet
(creator_code:org_t)
Related titles
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In:Journal of Biological Chemistry284:40, s. 27533-275430021-92581083-351X
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