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The FAT epidemic: a gene family frequently mutated across multiple human cancer types.

Morris LG, Ramaswami D, Chan TA - Cell Cycle (2013)

View Article: PubMed Central - PubMed

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In recent years, mutational surveys published by our group, The Cancer Genome Atlas, and others have revealed highly prevalent mutations and deletions targeting an intriguing family of genes encoding transmembrane proteins: the FAT family (FAT1, FAT2, FAT3 and FAT4)... Both genes harbor recurrent mutations and deletions in multiple types of human cancer, including glioblastoma (FAT1, 20%), colorectal (FAT1, 9%; FAT4, 20%), head and neck squamous cell (FAT1, 12%; FAT4, 10%), gastric (FAT4, 20%), serous ovarian (FAT1, 7%; FAT4, 3%) and pancreatic (FAT1, 4%; FAT4, 8%) cancers... Both in vitro and in vivo, depletion of FAT1 leads to markedly accelerated cell growth and proliferation, while expression of FAT1 robustly suppresses tumor growth... These growth-suppressive effects are abrogated when mutations observed in tumors are present... Just as classical cadherin proteins can bind to β-catenin and regulate its transcriptional activity, FAT1 also binds β-catenin and limits its translocation to the cell nucleus... Mutations in FAT1’s intracytoplasmic domain result in a loss of this ability to regulate β-catenin... Therefore, loss of FAT1 in cells activates the Wnt signaling pathway, unleashing β-catenin-dependent transcriptional activity and upregulating pro-growth wnt transcriptional targets... Consistent with this, primary cancer samples with FAT1 alterations are defined by significant enhancement of Wnt signaling... New data now implicates FAT1 mutation as a driver of Wnt activation in many of these tumors, and point to FAT1 as a potential molecular determinant for guiding use of new small-molecule inhibitors of Wnt signaling... Interestingly, FAT1 appears to play multiple, seemingly opposing, roles in development and cell growth... While the protein has a strong tumor-suppressive effect, it also binds to Ena/VASP, thereby promoting actin polymerization and cell motility... For these reasons, it is conceivable that the function of FAT1 in tumorigenesis is multifaceted, such that the gene may not operate as a tumor suppressor via the same mechanisms in all cellular contexts... FAT2 and FAT3 have not been well characterized to date, although each gene has been observed to be undergo mutation in approximately 10% of colorectal and lung squamous cell cancers... These two genes have more similarity to FAT1 than FAT4, but it remains to be seen whether these protocadherins are also able to modulate Wnt signaling.

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Figure 1. Model of FAT1 function. When FAT1 is present, β-catenin is held at the cell membrane. When FAT1 is inactivated by mutation or deleted in cancers, an excess of β-catenin is present in the cytoplasm. Some β-catenin is then able to enter the nucleus and cooperate with TCF transcription factors to activate gene expression of Wnt target genes. The APC/GSK-3/Axin complex can potentially target β-catenin for degradation. However, excess β-catenin caused by FAT1 inactivation may not all be degraded by the APC/GSK-3/Axin complex or the complex may not be as active in non-colorectal cells.
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Figure 1: Figure 1. Model of FAT1 function. When FAT1 is present, β-catenin is held at the cell membrane. When FAT1 is inactivated by mutation or deleted in cancers, an excess of β-catenin is present in the cytoplasm. Some β-catenin is then able to enter the nucleus and cooperate with TCF transcription factors to activate gene expression of Wnt target genes. The APC/GSK-3/Axin complex can potentially target β-catenin for degradation. However, excess β-catenin caused by FAT1 inactivation may not all be degraded by the APC/GSK-3/Axin complex or the complex may not be as active in non-colorectal cells.

Mentions: FAT2 and FAT3 have not been well characterized to date, although each gene has been observed to be undergo mutation in approximately 10% of colorectal and lung squamous cell cancers.5,6 These two genes have more similarity to FAT1 than FAT4,8 but it remains to be seen whether these protocadherins are also able to modulate Wnt signaling. As additional mutational data in diverse human cancers is reported, the precise implications of the recurrent alterations targeting these intriguing, large, ancient proteins will be more thoroughly illuminated. (Fig. 1)


The FAT epidemic: a gene family frequently mutated across multiple human cancer types.

Morris LG, Ramaswami D, Chan TA - Cell Cycle (2013)

Figure 1. Model of FAT1 function. When FAT1 is present, β-catenin is held at the cell membrane. When FAT1 is inactivated by mutation or deleted in cancers, an excess of β-catenin is present in the cytoplasm. Some β-catenin is then able to enter the nucleus and cooperate with TCF transcription factors to activate gene expression of Wnt target genes. The APC/GSK-3/Axin complex can potentially target β-catenin for degradation. However, excess β-catenin caused by FAT1 inactivation may not all be degraded by the APC/GSK-3/Axin complex or the complex may not be as active in non-colorectal cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3646852&req=5

Figure 1: Figure 1. Model of FAT1 function. When FAT1 is present, β-catenin is held at the cell membrane. When FAT1 is inactivated by mutation or deleted in cancers, an excess of β-catenin is present in the cytoplasm. Some β-catenin is then able to enter the nucleus and cooperate with TCF transcription factors to activate gene expression of Wnt target genes. The APC/GSK-3/Axin complex can potentially target β-catenin for degradation. However, excess β-catenin caused by FAT1 inactivation may not all be degraded by the APC/GSK-3/Axin complex or the complex may not be as active in non-colorectal cells.
Mentions: FAT2 and FAT3 have not been well characterized to date, although each gene has been observed to be undergo mutation in approximately 10% of colorectal and lung squamous cell cancers.5,6 These two genes have more similarity to FAT1 than FAT4,8 but it remains to be seen whether these protocadherins are also able to modulate Wnt signaling. As additional mutational data in diverse human cancers is reported, the precise implications of the recurrent alterations targeting these intriguing, large, ancient proteins will be more thoroughly illuminated. (Fig. 1)

View Article: PubMed Central - PubMed

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

In recent years, mutational surveys published by our group, The Cancer Genome Atlas, and others have revealed highly prevalent mutations and deletions targeting an intriguing family of genes encoding transmembrane proteins: the FAT family (FAT1, FAT2, FAT3 and FAT4)... Both genes harbor recurrent mutations and deletions in multiple types of human cancer, including glioblastoma (FAT1, 20%), colorectal (FAT1, 9%; FAT4, 20%), head and neck squamous cell (FAT1, 12%; FAT4, 10%), gastric (FAT4, 20%), serous ovarian (FAT1, 7%; FAT4, 3%) and pancreatic (FAT1, 4%; FAT4, 8%) cancers... Both in vitro and in vivo, depletion of FAT1 leads to markedly accelerated cell growth and proliferation, while expression of FAT1 robustly suppresses tumor growth... These growth-suppressive effects are abrogated when mutations observed in tumors are present... Just as classical cadherin proteins can bind to β-catenin and regulate its transcriptional activity, FAT1 also binds β-catenin and limits its translocation to the cell nucleus... Mutations in FAT1’s intracytoplasmic domain result in a loss of this ability to regulate β-catenin... Therefore, loss of FAT1 in cells activates the Wnt signaling pathway, unleashing β-catenin-dependent transcriptional activity and upregulating pro-growth wnt transcriptional targets... Consistent with this, primary cancer samples with FAT1 alterations are defined by significant enhancement of Wnt signaling... New data now implicates FAT1 mutation as a driver of Wnt activation in many of these tumors, and point to FAT1 as a potential molecular determinant for guiding use of new small-molecule inhibitors of Wnt signaling... Interestingly, FAT1 appears to play multiple, seemingly opposing, roles in development and cell growth... While the protein has a strong tumor-suppressive effect, it also binds to Ena/VASP, thereby promoting actin polymerization and cell motility... For these reasons, it is conceivable that the function of FAT1 in tumorigenesis is multifaceted, such that the gene may not operate as a tumor suppressor via the same mechanisms in all cellular contexts... FAT2 and FAT3 have not been well characterized to date, although each gene has been observed to be undergo mutation in approximately 10% of colorectal and lung squamous cell cancers... These two genes have more similarity to FAT1 than FAT4, but it remains to be seen whether these protocadherins are also able to modulate Wnt signaling.

Show MeSH
Related in: MedlinePlus