SRC-induced disassembly of adherens junctions requires localized phosphorylation and degradation of the rac activator tiam1.
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.
Woodcock
Simon A
SA
Cell Signalling Group, Cancer Research UK Paterson Institute for Cancer Research, University of Manchester, Manchester, UK.
Rooney
Claire
C
Liontos
Michalis
M
Connolly
Yvonne
Y
Zoumpourlis
Vassilis
V
Whetton
Anthony D
AD
Gorgoulis
Vassilis G
VG
Malliri
Angeliki
A
D022005:Adherens Junctions / Q000201:enzymology*; D000818:Animals; D002154:Calpain / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement; D003001:Cloning, Molecular; D004285:Dogs; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051380:GRB2 Adaptor Protein / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology; D015688:Oncogene Protein pp60(v-src) / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D051575:Proto-Oncogene Proteins c-yes / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020837:SOS1 Protein / Q000378:metabolism; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D013997:Time Factors; D014162:Transfection; D014443:Tyrosine; D018909:src Homology Domains; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
D051380:GRB2 Adaptor Protein; D020662:Guanine Nucleotide Exchange Factors; D016271:Proto-Oncogene Proteins c-myc; D011993:Recombinant Fusion Proteins; D020837:SOS1 Protein; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C087334:TIAM1 protein, human; C513260:Tiam1 protein, mouse; D014443:Tyrosine; D015688:Oncogene Protein pp60(v-src); D051575:Proto-Oncogene Proteins c-yes; D016392:Proto-Oncogene Proteins pp60(c-src); D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D002154:Calpain; C410233:Capns1 protein, mouse