Mammalian Fat1 cadherin regulates actin dynamics and cell–cell contact

Tanoue, Takuji; Takeichi, Masatoshi

doi:10.1083/jcb.200403006

Cited by 148 publications

(179 citation statements)

References 56 publications

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“…All bipolar disorder-associated SNPs fall within an 8.7 kb LD block of FAT, which encodes the EVH1 domain of the FAT protein. The Ena/VASP protein ENAH has been implicated as a downstream effector of FAT 46 and was found in our analysis to be significantly differentially regulated in response to bipolar disorder therapeutic drugs. ENAH maps to chromosome 1q42, a region that has been strongly implicated in linkage studies as harboring a bipolar disorder susceptibility gene.…”

Section: Discussionmentioning

confidence: 70%

“…45,46 The Ena/VASP proteins are thought to play redundant roles in regulating actin cytoskeletal dynamics (reviewed by Renfranz and Beckerle 47 ). Interaction between FAT and Ena/VASP proteins is mediated via an EVH1 domain.…”

Section: Resultsmentioning

confidence: 99%

“…45,46 This interaction is mediated via an EVH1 domain. All bipolar disorder-associated SNPs fall within an 8.7 kb LD block of FAT, which encodes the EVH1 domain of the FAT protein.…”

Section: Discussionmentioning

confidence: 99%

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Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele

et al. 2006

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A susceptibility locus for bipolar disorder was previously localized to chromosome 4q35 by genetic linkage analysis. We have applied a positional cloning strategy, combined with association analysis and provide evidence that a cadherin gene, FAT, confers susceptibility to bipolar disorder in four independent cohorts (allelic P-values range from 0.003 to 0.024). In two case-control cohorts, association was identified among bipolar cases with a family history of psychiatric illness, whereas in two cohorts of parent-proband trios, association was identified among bipolar cases who had exhibited psychosis. Pooled analysis of the case-control cohort data further supported association (P = 0.0002, summary odds ratio = 2.31, 95% CI: 1.49-3.59). We localized the bipolar-associated region of the FAT gene to an interval that encodes an intracellular EVH1 domain, a domain that interacts with Ena/VASP proteins, as well as putative b-catenin binding sites. Expression of Fat, Catnb (b-catenin), and the three genes (Enah, Evl and Vasp) encoding the Ena/VASP proteins, were investigated in mice following administration of the mood-stabilizing drugs, lithium and valproate. Fat was shown to be significantly downregulated (P = 0.027), and Catnb and Enah were significantly upregulated (P = 0.0003 and 0.005, respectively), in response to therapeutic doses of lithium. Using a protein interaction map, the expression of genes encoding murine homologs of the FAT (ft)-interacting proteins was investigated. Of 14 interacting molecules that showed expression following microarray analysis (including several members of the Wnt signaling pathway), eight showed significantly altered expression in response to therapeutic doses of lithium (binomial P = 0.004). Together, these data provide convergent evidence that FAT and its protein partners may be components of a molecular pathway involved in susceptibility to bipolar disorder.

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Section: Discussionmentioning

confidence: 70%

Section: Resultsmentioning

confidence: 99%

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Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele

et al. 2006

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“…40 The Wnt/b-catenin pathways have been shown to be essential in the development of all hematopoietic cells, and mutations in this pathway lead to leukemia. 41 In addition, the t(1;19)(E2A-PBX1) translocation has been shown to induce high expression of Wnt16 and to regulate leukemia --stroma interactions, with b-catenin expression highly expressed and localized at the cell membrane.…”

Section: Discussionmentioning

confidence: 99%

The Fat1 cadherin is overexpressed and an independent prognostic factor for survival in paired diagnosis–relapse samples of precursor B-cell acute lymphoblastic leukemia

et al. 2011

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Improved survival of patients with acute lymphoblastic leukemia (ALL) has emerged from identifying new prognostic markers; however, 20% of children still suffer recurrence. Previously, the altered expression of Fat1 cadherin has been implicated in a number of solid tumors. In this report, in vitro analysis shows that Fat1 protein is expressed by a range of leukemia cell lines, but not by normal peripheral blood (PB) and bone marrow (BM) cells from healthy donors. In silico analysis of expression of array data from clinical leukemias found significant levels of Fat1 transcript in 11% of acute myeloid leukemia, 29% and 63% of ALL of B and T lineages, respectively, and little or no transcript present in normal PB or BM. Furthermore, in two independent studies of matched diagnosis --relapse of precursor B-cell (preB) ALL pediatric samples (n ¼ 32 and n ¼ 27), the level of Fat1 mRNA expression was prognostic at the time of diagnosis. High Fat1 mRNA expression was predictive of shorter relapse-free and overall survival, independent of other traditional prognostic markers, including white blood cell count, sex and age. The data presented demonstrate that Fat1 expression in preB-ALL has a role in the emergence of relapse and could provide a suitable therapeutic target in high-risk preB-ALL.Leukemia ( INTRODUCTIONChildren with acute lymphoblastic leukemia (ALL) continue to suffer a 20% incidence of relapse after treatment with the best available therapy. High-resolution genomic profiling, including analysis of single-nucleotide polymorphisms and copy number abnormalities, has greatly aided an understanding of the molecular mechanisms underlying treatment outcome, therapy response and the biology of relapse. 1,2 For precursor B-cell (preB) ALL, genomic studies have shown that copy number abnormalities in genes involved in lymphoid differentiation and cell cycle control are common, with deletions, or part thereof, found in PAX5, EBF1, IKZF1, TCF-4, CDKN2A and RB1. 2 --5 Recent reports also indicate that deletions and nonsense mutations of the IKZF1 gene are significantly associated with poor relapse-free and overall survival rates in preB-ALL. 6 However, in light of these studies, questions remain on the biology of relapse, with marker analysis complicated by the fact that phenotypic shifts in preB-ALL blasts can occur between diagnostic and post-chemotherapy or relapse samples. 7 Those cells that give rise to relapse in some cases appear to be selected during treatment, with clonal evolution occurring of a minor subclone present at diagnosis rather than simply being the development of chemotherapeutic resistance of the original leukemic clone. 8,9 The inherent genetic heterogeneity

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“…This gene product (hFAT1 protocadherin: FAT1) regulates actin dynamics, cell to cell contact and cell polarity and associate with Ena/VASP, Homer 3, and β-catenin (1)(2)(3). On the other hand, FAT1 is involved in the structure and function of the glomerular slit by podocytes (4), and the development of the brain as well as its function, especially regarding its association with the susceptibility to bipolar affective disorder (5,6).…”

Section: Introductionmentioning

confidence: 99%

Human FAT1 cadherin controls cell migration and invasion of oral squamous cell carcinoma through the localization of β-catenin

Miyazaki¹

2011

Oncol Rep

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Abstract. FAt1 [Homo sapiens FAt tumor suppressor homolog 1 (Drosophila)] is an intrinsic membrane protein classified as a member of the cadherin superfamily. The FAT1 gene is a tumor suppressor in humans as well as being the pivotal gene for cell morphogenesis and migration. Deletion of this gene could play a role in the characteristics of oral squamous cell carcinomas (OSCCs), involving cell adhesion, migration and/ or invasion. This study investigated the mechanisms by which FAT1 is involved in the biological behavior of OSCCs. First, a rat monoclonal antibody was developed against a FAT1 intracellular domain epitope, and used for an immunohistochemical study of FAT1 in clinically obtained OSCC samples. FAT1 was localized at lamellipodial edges or cell-cell boundaries in normal cells and well differentiated OSCCs, but showed a diffuse cytoplasmic and nuclear distribution in moderatelypoorly differentiated OSCCs. FAT1-siRNA was transfected into OSCCs resulting in a drastic inhibition of cell migration and invasion based on the suppression of FAT1 expression and disorganized localization of β-catenin which is associated with cell polarity and migration. These results suggested that FAT1 may be involved in the migration and invasion mechanisms of OSCCs and, therefore, it could be an important target for the development of new therapeutic strategies.

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Mammalian Fat1 cadherin regulates actin dynamics and cell–cell contact

Cited by 148 publications

References 56 publications

Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele

Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele

The Fat1 cadherin is overexpressed and an independent prognostic factor for survival in paired diagnosis–relapse samples of precursor B-cell acute lymphoblastic leukemia

Human FAT1 cadherin controls cell migration and invasion of oral squamous cell carcinoma through the localization of β-catenin

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