The Fat1 cadherin integrates vascular smooth muscle cell growth and migration signals

Hou, Rong; Li, Liming; Anees, Syed; Hiroyasu, Shungo; Sibinga, Nicholas E.S.

doi:10.1083/jcb.200508121

Cited by 92 publications

(136 citation statements)

References 46 publications

Supporting

Mentioning

131

Contrasting

Order By: Relevance

“…46 Although this translocation is no longer associated with poor prognosis in pediatric patients due to new and intensified chemotherapy, 47,48 they do suffer from increased risk of central nervous system relapse. 49,50 Previous reports have established high Fat1 expression within the central nervous system and its importance for central nervous system development, 14,51,52 and we therefore speculate that high Fat1 expression associated with the t(1;19)(E2A-PBX1) translocation, together with the ability of the cytoplasmic tail of Fat1 to directly bind b-catenin, 53 may provide another potential mechanism whereby ectopic Fat1 expression can either aid central nervous system infiltration or stabilize leukemia --stroma interactions with its unknown extracellular ligand. Finally, our laboratory has recently shown that the Fat1 protein is expressed as both an unprocessed full-length protein and furin-processed heterodimer on the surface of melanoma cells.…”

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

View full text Add to dashboard Cite

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

show abstract

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

View full text Add to dashboard Cite

show abstract

“…In addition, FAT1 indirectly regulates cell proliferation; Hou et al demonstrated that the inhibition of FAT1 expression promotes cell proliferation whereas the overexpression of FAT1 suppresses proliferation in vascular muscle cells (10). Therefore, the inhibition of FAT1 expression was expected to increase the cell proliferation in the OSCCs as well.…”

Section: Discussionmentioning

confidence: 99%

“…The cytoplasmic domain of FAT1 binds to β-catenin and plays a pivotal role in cell migration, polarization and morphogenesis (3,(10)(11)(12)(13)(14)(15)(16). Therefore, the deletion of this gene could implicate the characteristics and biological behavior of OSCCs that involve cell adhesion, migration and/or invasion, which might result in poor prognosis.…”

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

View full text Add to dashboard Cite

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.

show abstract

“…In addition to this, in the same experiment, we also tested the effect of growth factor stimulation by increasing the concentration of serum because the expression of FAT1 can be stimulated by serum in vascular smooth muscle cells (16). Fig.…”

Section: Fat1 Is Proteolytically Processed Before Achieving Cell Surfmentioning

confidence: 99%

Dual Processing of FAT1 Cadherin Protein by Human Melanoma Cells Generates Distinct Protein Products

Sadeqzadeh

Bock

Zhang

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

The giant cadherin FAT1 is one of four vertebrate orthologues of the Drosophila tumor suppressor fat. It engages in several functions, including cell polarity and migration, and in Hippo signaling during development. Homozygous deletions in oral cancer suggest that FAT1 may play a tumor suppressor role, although overexpression of FAT1 has been reported in some other cancers. Here we show using Northern blotting that human melanoma cell lines variably but universally express FAT1 and less commonly FAT2, FAT3, and FAT4. Both normal melanocytes and keratinocytes also express comparable FAT1 mRNA relative to melanoma cells. Analysis of the protein processing of FAT1 in keratinocytes revealed that, like Drosophila FAT, human FAT1 is cleaved into a non-covalent heterodimer before achieving cell surface expression. The use of inhibitors also established that such cleavage requires the proprotein convertase furin. However, in melanoma cells, the non-cleaved proform of FAT1 is also expressed at the cell surface together with the furin-cleaved heterodimer. Moreover, furin-independent processing generates a potentially functional proteolytic product in melanoma cells, a persistent 65-kDa membrane-bound cytoplasmic fragment no longer in association with the extracellular fragment. In vitro localization studies of FAT1 showed that melanoma cells display high levels of cytosolic FAT1 protein, whereas keratinocytes, despite comparable FAT1 expression levels, exhibited mainly cell-cell junctional staining. Such differences in protein distribution appear to reconcile with the different protein products generated by dual FAT1 processing. We suggest that the uncleaved FAT1 could promote altered signaling, and the novel products of alternate processing provide a dominant negative function in melanoma.

show abstract

The Fat1 cadherin integrates vascular smooth muscle cell growth and migration signals

Cited by 92 publications

References 46 publications

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

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

Dual Processing of FAT1 Cadherin Protein by Human Melanoma Cells Generates Distinct Protein Products

Contact Info

Product

Resources

About