AMER1 regulates the distribution of the tumor suppressor APC between microtubules and the plasma membrane

Grohmann, Annette; Tanneberger, Kristina; Alzner, Astrid; Schneikert, Jean; Behrens, Jürgen

doi:10.1242/jcs.011320

Cited by 83 publications

(160 citation statements)

References 39 publications

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“…This suggests that the ability of WTX to induce apoptosis is not related to its physical interaction to b-catenin. Again consistent with a prior study (Grohmann et al, 2007), EGFP-WTX-FL was prominent at the plasma membrane, potentially because of the action through two phosphatidylinositol bisphosphatebinding domains (amino acids 2-142 and 143-209) ( Figure 1d). As WTX566-1135 also induced apoptosis, WTX-mediated apoptosis may be independent of plasma membrane localization as well.…”

Section: Resultssupporting

confidence: 91%

“…WTX may have other functions as well. The N-terminus of WTX protein contains two distinct phosphatidylinositol bisphosphate-binding domains, which renders its localization to the plasma membrane (Grohmann et al, 2007). WTX also interacts with the adenomatous polyposis coli (APC) protein and attracts APC to the plasma membrane.…”

Section: Introductionmentioning

confidence: 99%

“…WTX also interacts with the adenomatous polyposis coli (APC) protein and attracts APC to the plasma membrane. This prevents the association of APC with microtubules, affecting the functional roles of APC in cell adhesion and migration (Grohmann et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Functional characterization of Wilms tumor-suppressor WTX and tumor-associated mutants

et al. 2010

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The WTX, Wilms tumor-associated tumor-suppressor gene, is present on the X chromosome and a single WTX mutation may be sufficient to promote carcinogenesis. Unlike the WT1 tumor suppressor, a transcription factor, WTX lacks conserved functional protein domains. To study the function of WTX, we constructed inducible cell lines expressing WTX and tumor-associated WTX mutants. Induction of WTX inhibited cell growth and caused G 1 /G 0 arrest. In contrast, a short, tumorassociated truncation mutant of WTX358 only slightly inhibited cell growth without a significant cell-cycle arrest, although expression of a longer truncation mutant WTX565 led to the growth inhibition and cell-cycle arrest to a similar extent as wild-type WTX. Like WT1, WTX slowed growth and caused cell-cycle arrest through p21 induction. Gene expression profiling showed that these two tumorsuppressors regulated genes in similar pathways, including those implicated in control of the cellular growth, cell cycle, cell death, cancer and cardiovascular system development. When gene expression changes mediated by wild-type WTX were compared with those affected by mutant forms, WTX565 showed a 55% overlap (228 genes) in differentially regulated genes, whereas WTX358 regulated only two genes affected by wild-type WTX, implying that amino-acid residues 358-561 are critical for WTX function.

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Section: Resultssupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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Functional characterization of Wilms tumor-suppressor WTX and tumor-associated mutants

et al. 2010

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“…WTX appears to act as an unusual tumour suppressor gene, in which it is inactivated by one-hit mutational events: mutations in the single X chromosome in tumours from males and the active X chromosome in tumours from females cause inactivation of this gene (Rivera et al, 2007;Perotti et al, 2008;Ruteshouser et al, 2008). Recently, WTX was found to form a complex with AXIN, APC (adenomatous polyposis coli) and b-catenin in the cytoplasm (Grohmann et al, 2007;Major et al, 2007). WTX was shown to antagonize WNT/b-catenin signalling, as WTX interacted directly with b-catenin to promote its ubiquitination and degradation (Major et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…Mutations in CTNNB1 and WTX were therefore proposed to be not functionally redundant (Ruteshouser et al, 2008), supporting the notion that b-catenin and WTX act in a common pathway. Alternatively, WTX has been independently reported as an APC-interacting protein controlling the subcellular distribution of APC between the cell membrane and the microtubule of epithelial cells (Grohmann et al, 2007), suggesting another tumour suppressor function of WTX independent of WNT signalling.…”

Section: Introductionmentioning

confidence: 99%

Canonical WNT signalling determines lineage specificity in Wilms tumour

et al. 2009

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Wilms tumours (WTs) have two distinct types of histology with or without ectopic mesenchymal elements, suggesting that WTs arise from either the mesenchymal or epithelial nephrogenic lineages. Regardless of the presence or absence of CTNNB1 mutations, nuclear accumulation of b-catenin is often observed in WTs with ectopic mesenchymal elements. Here, we addressed the relationship between the WNT-signalling pathway and lineage in WTs by examining CTNNB1 and WT1 mutations, nuclear accumulation of b-catenin, tumour histology and gene expression profiles. In addition, we screened for mutations in WTX, which has been proposed to be a negative regulator of the canonical WNT-signalling pathway. Unsupervised clustering analysis identified two classes of tumours: mesenchymal lineage WNT-dependent tumours, and epithelial lineage WNT-independent tumours. In contrast to the mesenchymal lineage specificity of CTNNB1 mutations, WTX mutations were surprisingly observed in both lineages. WTX-mutant WTs with ectopic mesenchymal elements had nuclear accumulation of b-catenin, upregulation of WNT target genes and an association with CTNNB1 mutations in exon 7 or 8. However, epithelial lineage WTs with WTX mutations had no indications of active WNT signalling, suggesting that the involvement of WTX in the WNT-signalling pathway may be lineage dependent, and that WTX may have an alternative function to its role in the canonical WNT-signalling pathway.

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The male phenotype in osteopathia striata congenita with cranial sclerosis

Holman

Daniel

Jenkins

et al. 2011

American J of Med Genetics Pt A

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Osteopathia striata with cranial sclerosis (OSCS) is an X-linked disease caused by truncating mutations in WTX. Females exhibit sclerotic striations on the long bones, cranial sclerosis, and craniofacial dysmorphism. Males with OSCS have significant skeletal sclerosis, do not have striations but do display a more severe phenotype commonly associated with gross structural malformations, patterning defects, and significant pre- and postnatal lethality. The recent description of mutations in WTX underlying OSCS has led to the identification of a milder, survivable phenotype in males. Individuals with this presentation can have, in addition to skeletal sclerosis, Hirschsprung disease, joint contractures, cardiomyopathy, and neuromuscular anomalies. A diagnosis of OSCS should be considered in males with macrocephaly, skeletal sclerosis that is most marked in the cranium and the absence of metaphyseal striations. The observation of striations in males may be indicative of a WTX mutation in a mosaic state supporting the contention that this sign in females is indicative of the differential lyonization of cells in the osteoblastic lineage.

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AMER1 regulates the distribution of the tumor suppressor APC between microtubules and the plasma membrane

Abstract: SummaryAMER1 regulates the distribution of the tumor suppressor APC between microtubules and the plasma membrane

Cited by 83 publications

References 39 publications

Functional characterization of Wilms tumor-suppressor WTX and tumor-associated mutants

Functional characterization of Wilms tumor-suppressor WTX and tumor-associated mutants

Canonical WNT signalling determines lineage specificity in Wilms tumour

The male phenotype in osteopathia striata congenita with cranial sclerosis

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