Src-Induced Disassembly of Adherens Junctions Requires Localized Phosphorylation and Degradation of the Rac Activator Tiam1

Woodcock, Simon; Rooney, Claire; Liontos, Michalis; Connolly, Yvonne; Zoumpourlis, Vassilis; Whetton, Anthony D.; Gorgoulis, Vassilis G.; Malliri, Angeliki

doi:10.1016/j.molcel.2009.02.012

Cited by 79 publications

(78 citation statements)

References 38 publications

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“…Cell lysates were obtained by centrifugation at 14,000 ϫ g for 15 min, and protein concentration was determined by Bradford protein assay (Beyotime). 20 l of cell lysates (about 30 g of protein) were firstly mixed with 70 l of reaction buffer and then incubated with 10 l of acetylAsp-Glu-Val-Asp p-nitroanilide (2 mM) in a 96-well plate for 2 h at 37°C. Caspase 3 activity was measured through the substrate p-nitroanilide at an absorbance at 405 nm in a microplate spectrophotometer (Thermo).…”

Section: Methodsmentioning

confidence: 99%

“…T cell lymphoma invasion and metastasis 1 (Tiam1) serves as a specific GEF for Rho GTPase Rac1 (16). Although it has been well established that Tiam1 plays important roles in tumor progression and metastasis (17)(18)(19)(20), the specific mechanisms regulating its activity and protein stability are far from clear (21,22). It has been reported that Src-induced adherens junction disassembly and cell migration involve phosphorylation and degradation of Tiam1, likely through calpain proteases (20).…”

mentioning

confidence: 99%

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DNA Damage Induces the Accumulation of Tiam1 by Blocking β-TrCP-dependent Degradation

Zhu

Fan

Ding

et al. 2014

Journal of Biological Chemistry

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Background: DNA damage-induced activation of the Rac1/JNK cascade is required for apoptosis. Results: Upon chemotherapeutic drug treatment, Tiam1, a Rac1-specific GEF, is accumulated through inhibition of CK1/ ␤-TrCP-mediated degradation. Conclusion: DNA damage induces up-regulation of Tiam1, which contributes to Rac1/JNK activation. Significance: This work uncovers how the Rac1/JNK cascade is activated upon DNA damage signaling and subsequent apoptosis.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

DNA Damage Induces the Accumulation of Tiam1 by Blocking β-TrCP-dependent Degradation

Zhu

Fan

Ding

et al. 2014

Journal of Biological Chemistry

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“…Several signaling pathways and proteases have been reported to be involved in the degradation of Tiam1 protein, in particular activation of calcium-dependent calpain proteases (Qi et al, 2001;Woodcock et al, 2009). Induction of senescence in various cell types triggers a DNA damage response that then triggers activation of calpain proteases (Demarchi et al, 2010).…”

Section: Rmfs Undergo Stress-induced Senescencementioning

confidence: 99%

“…Treatment of cultured cells with the calpain inhibitor ALLN during induced senescence led to toxic cell death at all doses tested. Therefore, we performed an in vitro Tiam1 cleavage assay based on similar in vitro protease assays reported previously (Li et al, 1997;Juo et al, 1998;Qi et al, 2001;Woodcock et al, 2009). Tiam1 immunoprecipitates from cells with exogenous Tiam1 expression Pre, pre-senescent cells; H2O2, hydrogen peroxide; Bleo, bleomycin; C, control pBabe RMF; Lys, loading control lysate for position of the full-length Tiam1 band, also indicated by an arrow.…”

Section: Rmfs Undergo Stress-induced Senescencementioning

confidence: 99%

Tiam1-regulated osteopontin in senescent fibroblasts contributes to the migration and invasion of associated epithelial cells

Liu

Chase

et al. 2012

Journal of Cell Science

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SummaryThe tumor microenvironment undergoes changes concurrent with neoplastic progression. Cancer incidence increases with aging and is associated with tissue accumulation of senescent cells. Senescent fibroblasts are thought to contribute to tumor development in aging tissues. We have shown that fibroblasts deficient in the Rac exchange factor Tiam1 promote invasion and metastasis of associated epithelial tumor cells. Here, we use a three-dimensional culture model of cellular invasiveness to outline several steps underlying this effect. We find that stress-induced senescence induces decreased fibroblast Tiam1 protein levels and increased osteopontin levels, and that senescent fibroblast lysates induce Tiam1 protein degradation in a calcium-and calpain-dependent fashion. Changes in fibroblast Tiam1 protein levels induce converse changes in osteopontin mRNA and protein. Senescent fibroblasts induce increased invasion and migration in co-cultured mammary epithelial cells. These effects in epithelial cells are ameliorated by either increasing fibroblast Tiam1 or decreasing fibroblast osteopontin. Finally, in seeded cell migration assays we find that either senescent or Tiam1-deficient fibroblasts induce increased epithelial cell migration that is dependent on fibroblast secretion of osteopontin. These findings indicate that one mechanism by which senescent fibroblasts promote neoplastic progression in associated tumors is through degradation of fibroblast Tiam1 protein and the consequent increase in secretion of osteopontin by fibroblasts.

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“…Tyrosine phosphorylation of E-cadherin by Src targets it for ubiquitination-dependent endocytosis and degradation, thus limiting its availability at cell-cell contacts (Behrens et al, 1993;Fujita et al, 2002;Palacios et al, 2005). Tyrosine phosphorylation of other AJ-localized Src substrates such as the Rho-GEF, Tiam1, also contributes to the disruption of AJs in human malignancies (Woodcock et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Rack1 promotes epithelial cell–cell adhesion by regulating E-cadherin endocytosis

Swaminathan

Cartwright

2011

Oncogene

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E-cadherin and its cytoplasmic partners, catenins, mediate epithelial cell-cell adhesion. Disruption of this adhesion allows cancer cells to invade and metastasize. Aberrant activation of the Src tyrosine kinase disrupts cell-cell contacts through an E-cadherin/catenin-dependent mechanism. Previously we showed that Rack1 regulates the growth of colon cells by suppressing Src activity at G 1 and mitotic checkpoints, and in the intrinsic apoptotic and Akt cell survival pathways. Here we show that Rack1, partly by inhibiting Src, promotes cell-cell adhesion and reduces the invasive potential of colon cancer cells. Rack1 stabilizes E-cadherin and catenins at cell-cell contacts by inhibiting the Src phosphorylation of E-cadherin, the ubiquitination of E-cadherin by the E3 ligase Hakai and the endocytosis of E-cadherin. Upon depletion and restoration of extracellular calcium, Rack1 facilitates the re-assembly of E-cadherin-containing cell-cell contacts. Rack1 also blocks HGF-induced endocytosis of E-cadherin, disruption of cell-cell contacts and cell scatter. Our results uncover a novel function of Rack1 in maintaining the junctional homeostasis of intestinal epithelial cells by regulation of the Src-and growth factor-induced endocytosis of E-cadherin.

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Src-Induced Disassembly of Adherens Junctions Requires Localized Phosphorylation and Degradation of the Rac Activator Tiam1

Cited by 79 publications

References 38 publications

DNA Damage Induces the Accumulation of Tiam1 by Blocking β-TrCP-dependent Degradation

DNA Damage Induces the Accumulation of Tiam1 by Blocking β-TrCP-dependent Degradation

Tiam1-regulated osteopontin in senescent fibroblasts contributes to the migration and invasion of associated epithelial cells

Rack1 promotes epithelial cell–cell adhesion by regulating E-cadherin endocytosis

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