SRC-induced disassembly of adherens junctions requires localized phosphorylation and degradation of the rac activator tiam1.

2.50
Hdl Handle:
http://hdl.handle.net/10541/74023
Title:
SRC-induced disassembly of adherens junctions requires localized phosphorylation and degradation of the rac activator tiam1.
Authors:
Woodcock, Simon A; Rooney, Claire M; Liontos, Michalis; Connolly, Yvonne; Zoumpourlis, Vassilis; Whetton, Anthony D; Gorgoulis, Vassilis G; Malliri, Angeliki
Abstract:
The Rac activator Tiam1 is required for adherens junction (AJ) maintenance, and its depletion results in AJ disassembly. Conversely, the oncoprotein Src potently induces AJ disassembly and epithelial-mesenchymal transition (EMT). Here, we show that Tiam1 is phosphorylated on Y384 by Src. This occurs predominantly at AJs, is required for Src-induced AJ disassembly and cell migration, and creates a docking site on Tiam1 for Grb2. We find that Tiam1 is associated with ERK. Following recruitment of the Grb2-Sos1 complex, ERK becomes activated and triggers the localized degradation of Tiam1 at AJs, likely involving calpain proteases. Furthermore, we demonstrate that, in human tumors, Y384 phosphorylation positively correlates with Src activity, and total Tiam1 levels are inversely correlated. Thus, our data implicate Tiam1 phosphorylation and consequent degradation in Src-mediated EMT and resultant cell motility and establish a paradigm for regulating local concentrations of Rho-GEFs.
Affiliation:
Cell Signalling Group, Cancer Research UK Paterson Institute for Cancer Research, University of Manchester, Manchester, UK.
Citation:
SRC-induced disassembly of adherens junctions requires localized phosphorylation and degradation of the rac activator tiam1. 2009, 33 (5):639-53 Mol. Cell
Journal:
Molecular Cell
Issue Date:
13-Mar-2009
URI:
http://hdl.handle.net/10541/74023
DOI:
10.1016/j.molcel.2009.02.012
PubMed ID:
19285946
Type:
Article
Language:
en
ISSN:
1097-4164
Appears in Collections:
All Paterson Institute for Cancer Research; School of Cancer and Imaging Sciences; Cell Signalling; Molecular Biology Core Facility

Full metadata record

DC FieldValue Language
dc.contributor.authorWoodcock, Simon A-
dc.contributor.authorRooney, Claire M-
dc.contributor.authorLiontos, Michalis-
dc.contributor.authorConnolly, Yvonne-
dc.contributor.authorZoumpourlis, Vassilis-
dc.contributor.authorWhetton, Anthony D-
dc.contributor.authorGorgoulis, Vassilis G-
dc.contributor.authorMalliri, Angeliki-
dc.date.accessioned2009-07-15T16:21:25Z-
dc.date.available2009-07-15T16:21:25Z-
dc.date.issued2009-03-13-
dc.identifier.citationSRC-induced disassembly of adherens junctions requires localized phosphorylation and degradation of the rac activator tiam1. 2009, 33 (5):639-53 Mol. Cellen
dc.identifier.issn1097-4164-
dc.identifier.pmid19285946-
dc.identifier.doi10.1016/j.molcel.2009.02.012-
dc.identifier.urihttp://hdl.handle.net/10541/74023-
dc.description.abstractThe Rac activator Tiam1 is required for adherens junction (AJ) maintenance, and its depletion results in AJ disassembly. Conversely, the oncoprotein Src potently induces AJ disassembly and epithelial-mesenchymal transition (EMT). Here, we show that Tiam1 is phosphorylated on Y384 by Src. This occurs predominantly at AJs, is required for Src-induced AJ disassembly and cell migration, and creates a docking site on Tiam1 for Grb2. We find that Tiam1 is associated with ERK. Following recruitment of the Grb2-Sos1 complex, ERK becomes activated and triggers the localized degradation of Tiam1 at AJs, likely involving calpain proteases. Furthermore, we demonstrate that, in human tumors, Y384 phosphorylation positively correlates with Src activity, and total Tiam1 levels are inversely correlated. Thus, our data implicate Tiam1 phosphorylation and consequent degradation in Src-mediated EMT and resultant cell motility and establish a paradigm for regulating local concentrations of Rho-GEFs.en
dc.language.isoenen
dc.subjectCancer Invasivenessen
dc.subjectCanceren
dc.subject.meshAdherens Junctions-
dc.subject.meshAnimals-
dc.subject.meshCalpain-
dc.subject.meshCell Line-
dc.subject.meshCell Movement-
dc.subject.meshCloning, Molecular-
dc.subject.meshDogs-
dc.subject.meshExtracellular Signal-Regulated MAP Kinases-
dc.subject.meshGRB2 Adaptor Protein-
dc.subject.meshGuanine Nucleotide Exchange Factors-
dc.subject.meshHumans-
dc.subject.meshMAP Kinase Kinase Kinases-
dc.subject.meshMice-
dc.subject.meshMice, Knockout-
dc.subject.meshMutagenesis, Site-Directed-
dc.subject.meshMutation-
dc.subject.meshNeoplasm Invasiveness-
dc.subject.meshNeoplasms-
dc.subject.meshOncogene Protein pp60(v-src)-
dc.subject.meshPhosphorylation-
dc.subject.meshProtein Processing, Post-Translational-
dc.subject.meshProto-Oncogene Proteins c-myc-
dc.subject.meshProto-Oncogene Proteins c-yes-
dc.subject.meshProto-Oncogene Proteins pp60(c-src)-
dc.subject.meshRecombinant Fusion Proteins-
dc.subject.meshSOS1 Protein-
dc.subject.meshTime Factors-
dc.subject.meshTransfection-
dc.subject.meshTyrosine-
dc.subject.meshsrc Homology Domains-
dc.subject.meshsrc-Family Kinases-
dc.titleSRC-induced disassembly of adherens junctions requires localized phosphorylation and degradation of the rac activator tiam1.en
dc.typeArticleen
dc.contributor.departmentCell Signalling Group, Cancer Research UK Paterson Institute for Cancer Research, University of Manchester, Manchester, UK.en
dc.identifier.journalMolecular Cellen
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