Oncogenic Mutants of RON and MET Receptor Tyrosine Kinases Cause Activation of the β-Catenin Pathway

Danilkovitch‐Miagkova, Alla; Miagkov, Alexei; Skeel, Alison; Nakaigawa, Noboru; Zbar, Berton; Leonard, Edward J.

doi:10.1128/mcb.21.17.5857-5868.2001

Cited by 149 publications

(124 citation statements)

References 112 publications

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“…2 leads to loss of adherens junctional ␤-catenin and increased TCF-mediated gene transcription (Brembeck et al, 2004;Danilkovitch-Miagkova et al, 2001). But beyond these examples of the functional link between ␤-catenin's dual tasks (Nelson and Nusse, 2004), there is the question whether Wnt signaling influences the adhesive properties of cells.…”

Section: Discussionmentioning

confidence: 99%

Wingless signaling modulates cadherin-mediated cell adhesion inDrosophilaimaginal disc cells

Wodarz

Stewart

Nelson

et al. 2006

Journal of Cell Science

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Armadillo, the Drosophila homolog of β-catenin, plays a crucial role in both the Wingless signal transduction pathway and cadherin-mediated cell-cell adhesion, raising the possibility that Wg signaling affects cell adhesion. Here, we use a tissue culture system that allows conditional activation of the Wingless signaling pathway and modulation of E-cadherin expression levels. We show that activation of the Wingless signaling pathway leads to the accumulation of hypophosphorylated Armadillo in the cytoplasm and in cellular processes, and to a concomitant reduction of membrane-associated Armadillo. Activation of the Wingless pathway causes a loss of E-cadherin from the cell surface, reduced cell adhesion and increased spreading of the cells on the substratum. After the initial loss of E-cadherin from the cell surface, E-cadherin gene expression is increased by Wingless. We suggest that Wingless signaling causes changes in Armadillo levels and subcellular localization that result in a transient reduction of cadherin-mediated cell adhesion, thus facilitating cell shape changes, division and movement of cells in epithelial tissues.

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Section: Discussionmentioning

confidence: 99%

Wingless signaling modulates cadherin-mediated cell adhesion inDrosophilaimaginal disc cells

Wodarz

Stewart

Nelson

et al. 2006

Journal of Cell Science

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“…It is also known that tyrosine phosphorylation regulates the behavior of b-catenin. A number of RTKs such as those of epidermal growth factor (EGF; Hoschuetzky et al, 1994), insulin-like growth factor (IGF; Playford et al, 2000), and hepatocyte growth factor-like ligands (RON and MET;Danilkovitch-Miagkova et al, 2001) were shown to phosphorylate b-catenin and may lead to its nuclear translocation. Tyrosine residue 142 (Tyr 142; Piedra et al, 2003) phosphorylation is a common target.…”

Section: Resultsmentioning

confidence: 99%

The synovial sarcoma translocation protein SYT-SSX2 recruits β-catenin to the nucleus and associates with it in an active complex

et al. 2006

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Localization of b-catenin in the cell is a key determinant in its decision to function as a critical mediator of cell adhesion at the surface or a transcription activator in the nucleus. SYT-SSX2 is the fusion product of the chromosomal translocation, t(X;18)(p11.2;q11.2), which occurs in synovial sarcoma, a soft tissue tumor. SYT-SSX2 is known to associate with chromatin remodeling complexes and is proposed to be involved in controlling gene expression. We report that SYT-SSX2 plays a direct role in b-catenin regulation. When expressed in mammalian cells, SYT-SSX2-induced b-catenin recruitment to the nucleus. Interestingly, known target genes of canonical Wnt were not activated as a result of SYT-SSX2 expression, nor was the nuclear localization of b-catenin due to one of the signaling pathways normally implicated in this event. b-Catenin accumulation in the nucleus led to the formation of a transcriptionally active nuclear complex that contained SYT-SSX2 and b-catenin. More importantly, depletion of SYT-SSX2 in primary synovial sarcoma cells resulted in loss of nuclear b-catenin signal and a significant decrease in its signaling activity. These results unravel a novel pathway in the control of b-catenin cellular transport and strongly suggest that SYT-SSX2 contributes to tumor development, in part through b-catenin signaling.

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“…In six of seven cases with an Flt3-ITD, there was increased activity but this was not statistically significantly different from those without a mutation. It has been reported that the Wnt pathway can be activated by signalling via hepatocyte growth factor receptor tyrosine kinase (c-met) as well as by the Ron tyrosine kinase (Danilkovitch-Miagkova et al, 2001). It remains to be seen if Flt3 can directly activate this pathway.…”

Section: Cd34+ Patient Number --------------Aml Cases--------------mentioning

confidence: 99%

Constitutive activation of the Wnt/β-catenin signalling pathway in acute myeloid leukaemia

et al. 2005

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The b-catenin protein is at the core of the canonical Wnt signalling pathway. Wnt stimulation leads to b-catenin accumulation, nuclear translocation and interaction with T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors to regulate genes important for embryonic development and proliferation. Wnt/b-catenin can promote stem cell self-renewal and is dysregulated in colon carcinoma. We have examined the role of the Wnt pathway in the development of acute myeloid leukaemia (AML) and find that the b-catenin protein is readily detected in primary AML samples. Using transfection of a TCF/LEF reporter construct into primary AML cells and normal human progenitors, we find increased reporter activity in 16/25 leukaemia samples. Retrovirally mediated expression of a mutant active b-catenin in normal progenitors preserves CD34 expression and impairs myelomonocytic differentiation. Activation of TCF/LEF signalling decreases factor withdrawal-induced apoptosis of normal progenitors. A significant proportion of AML cases show aberrant expression of components of the Wnt pathway including Wnt-1, Wnt-2b and LEF-1. These results provide evidence for the involvement of the Wnt/b-catenin pathway in the pathogenesis of AML.

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Oncogenic Mutants of RON and MET Receptor Tyrosine Kinases Cause Activation of the β-Catenin Pathway

Cited by 149 publications

References 112 publications

Wingless signaling modulates cadherin-mediated cell adhesion inDrosophilaimaginal disc cells

Wingless signaling modulates cadherin-mediated cell adhesion inDrosophilaimaginal disc cells

The synovial sarcoma translocation protein SYT-SSX2 recruits β-catenin to the nucleus and associates with it in an active complex

Constitutive activation of the Wnt/β-catenin signalling pathway in acute myeloid leukaemia

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