Role of FAT1 in health and disease (Review)

Peng, Zizhen; Gong, Yanyu; Liang, Xin

doi:10.3892/ol.2021.12659

Cited by 47 publications

(27 citation statements)

References 120 publications

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“…FAT Atypical Cadherin 1 (FAT1) is a tumor suppressor that is involved in development, proliferation, migration, and invasion [63]. Its dysregulation has been implicated in many cancers.…”

Section: Fat1 Lossmentioning

confidence: 99%

Resistance to CDK4/6 Inhibitors in Estrogen Receptor-Positive Breast Cancer

Scheidemann

Shajahan-Haq

2021

IJMS

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Estrogen receptor-positive (ER+) breast cancer is the most common form of breast cancer. Antiestrogens were the first therapy aimed at treating this subtype, but resistance to these warranted the development of a new treatment option. CDK4/6 inhibitors address this problem by halting cell cycle progression in ER+ cells, and have proven to be successful in the clinic. Unfortunately, both intrinsic and acquired resistance to CDK4/6 inhibitors are common. Numerous mechanisms of how resistance occurs have been identified to date, including the activation of prominent growth signaling pathways, the loss of tumor-suppressive genes, and noncanonical cell cycle function. Many of these have been successfully targeted and demonstrate the ability to overcome resistance to CDK4/6 inhibitors in preclinical and clinical trials. Future studies should focus on the development of biomarkers so that patients likely to be resistant to CDK4/6 inhibition can initially be given alternative methods of treatment.

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“…FAT Atypical Cadherin 1 (FAT1) is a tumor suppressor that is involved in development, proliferation, migration, and invasion [63]. Its dysregulation has been implicated in many cancers.…”

Section: Fat1 Lossmentioning

confidence: 99%

Resistance to CDK4/6 Inhibitors in Estrogen Receptor-Positive Breast Cancer

Scheidemann

Shajahan-Haq

2021

IJMS

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“…The hypothesis that planar cell polarity (PCP) might be disturbed in meningiomas arises from the observation that a histological characteristic of meningiomas is the whorl formation of neoplastic arachnoid cells. This hypothesis has received some genetic support, as human FAT2, an ortholog of the Drosophila PCP pathway component Fat, has been implicated in meningioma [55] . Moreover, Fat protocadherens of the have been implicated in Hippo signaling [56] .…”

Section: Discussionmentioning

confidence: 99%

Furry is a component of the CCM3-GCKIII signaling pathway

Antwi-Adjei¹,

Burguete²,

Ghabrial³

2021

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Aim: Mutations in 3 genes encoding proteins of the Cerebral Cavernous Malformations (CCM) ternary complex cause autosomal dominant cerebral vascular disease. Targets of CCM complex regulation have been identified; however, the molecular mechanisms connecting CCM3 to these downstream effectors remain elusive. We aim to determine the mechanism of CCM3 action by using a Drosophila model to elucidate the signaling pathway downstream of CCM3. Previously, we showed that CCM3 and its binding partner, Germinal Center Kinase 3, are required in tracheal terminal cells to prevent tube morphogenesis defects. Further, we established that GCKIII phosphorylates and directly activates a downstream kinase, Tricornered (Drosophila STK38/38L ortholog). Here we aim to test whether Tricornered-associated scaffolding protein, Furry, is required for CCM3-GCKIII signaling. Methods:We utilized the FRT-FLP system to generate genetic mosaic Drosophila larvae and adults. Mitotic recombination was induced in embryos (trachea) or larvae (wing disc). The animals were heterozygous for the gene of interest (ccm3 or furry), but after recombination, homozygous mutant daughter cells were produced. In addition, the GAL4-UAS system was used to express dominant negative GCKIII in wing disc cells. Mutant cells were analyzed by brightfield and/or fluorescent microscopy.Results: We find that wing cells mutant for ccm3, or expressing dominant negative GCKIII, produce wing hair defects characteristic of mutations in tricornered and furry. Likewise, tracheal terminal cells mutant for furry produce tube dilation defects characteristic of cells mutant for ccm3 or GCKIII. Conclusion:CCM3 and GCKIII act upstream of Furry-Tricornered, suggesting the conservation from yeast of a Hippo-like signaling pathway that regulates morphogenesis. We speculate that some combination of Furry/Furrylike and STK38/38L are therefore likely to act downstream of CCM3 in endothelial cells.

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“…Similarly, Triml1 and Triml2 encode E3 ubiquitin ligase-like proteins with activity in pluripotency and a potential placental function (Zhang et al, 2020). By contrast, Fat1 encodes an atypical cadherin possessing elaborate later embryonic expression and pleiotropic roles in tissue morphogenesis, cell growth and migration, and cancer (Peng et al, 2021). Finally, the melatonin receptor-encoding Mtnr1a contributes to circadian rhythm through highly restricted expression in, for example, the Suprachiasmatic nucleus and pars tuberalis (Klosen et al, 2019).…”

Section: Rex1 and Fat1 Are Differentially Expressed Despite Sharing The Same Tadmentioning

confidence: 99%

“…Likewise, 24-76% of ATAC-peaks displayed no sequence conservation and were entirely species-specific. Thus, significant enhancer turnover occurred at the locus over time, perhaps to sustain or modify Fat1 activity which has diverse critical physiological functions (Peng et al, 2021). Nevertheless, between 5-27% of putative elements were functionally conserved between each species and this universally included the Fat1 promoter.…”

Section: Independent Rex1r Regulation Emerged Within Fat1's Ancient Tad Landscapementioning

confidence: 99%

Promoter repression and 3D-restructuring resolves divergent developmental gene expression in TADs

Ringel

Szabo

Chiariello

et al. 2021

Preprint

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Cohesin loop extrusion facilitates precise gene expression by continuously driving promoters to sample all enhancers located within the same topologically-associated domain (TAD). However, many TADs contain multiple genes with divergent expression patterns, thereby indicating additional forces further refine how enhancer activities are utilised. Here, we unravel the mechanisms enabling a new gene, Rex1, to emerge with divergent expression within the ancient Fat1 TAD in placental mammals. We show that such divergent expression is not determined by a strict enhancer-promoter compatibility code, intra-TAD position or nuclear envelope-attachment. Instead, TAD-restructuring in embryonic stem cells (ESCs) separates Rex1 and Fat1 with distinct proximal enhancers that independently drive their expression. By contrast, in later embryonic tissues, DNA methylation renders the inactive Rex1 promoter profoundly unresponsive to Fat1 enhancers within the intact TAD. Combined, these features adapted an ancient regulatory landscape during evolution to support two entirely independent Rex1 and Fat1 expression programs. Thus, rather than operating only as rigid blocks of co-regulated genes, TAD-regulatory landscapes can orchestrate complex divergent expression patterns in evolution.

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Role of FAT1 in health and disease (Review)

Cited by 47 publications

References 120 publications

Resistance to CDK4/6 Inhibitors in Estrogen Receptor-Positive Breast Cancer

Resistance to CDK4/6 Inhibitors in Estrogen Receptor-Positive Breast Cancer

Furry is a component of the CCM3-GCKIII signaling pathway

Promoter repression and 3D-restructuring resolves divergent developmental gene expression in TADs

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