Protocadherin FAT1 is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is encoded by the ''FAT1''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
Function
This gene is an
ortholog
Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a speci ...
of the ''
Drosophila
''Drosophila'' (), from Ancient Greek δρόσος (''drósos''), meaning "dew", and φίλος (''phílos''), meaning "loving", is a genus of fly, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or p ...
'' fat gene, which encodes a
tumor suppressor
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell (biology), cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results ...
essential for controlling cell proliferation during Drosophila development. The gene product is a member of the
cadherin
Cadherins (named for "calcium-dependent adhesion") are cell adhesion molecules important in forming adherens junctions that let cells adhere to each other. Cadherins are a class of type-1 transmembrane proteins, and they depend on calcium (Ca2+) ...
superfamily, a group of integral membrane proteins characterized by the presence of cadherin-type repeats. This gene is expressed at high levels in a number of fetal
epithelia
Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of many ...
. Transcript variants derived from alternative splicing and/or alternative promoter usage exist, but they have not been fully described.
The murine Fat1
knockout mouse
A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or " knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...
is not embryonically lethal but pups die within 48-hours due to the abnormal fusion of
podocyte foot processes
Podocytes are cells in Bowman's capsule in the kidneys that wrap around capillaries of the glomerulus. Podocytes make up the epithelial lining of Bowman's capsule, the third layer through which filtration of blood takes place. Bowman's capsule ...
within the kidney. These Fat1 knockout mice also showed partially penetrant but often severe midline defects including
holoprosencephaly
Holoprosencephaly (HPE) is a cephalic disorder in which the prosencephalon (the forebrain of the embryo) fails to Prenatal development, develop into two Cerebral hemisphere, hemispheres, typically occurring between the 18th and 28th day of gestati ...
,
microphthalmia
Microphthalmia (Greek: , ), also referred as microphthalmos, is a developmental disorder of the eye in which one (unilateral microphthalmia) or both (bilateral microphthalmia) eyes are abnormally small and have anatomic malformations. Microphthalm ...
-
anophthalmia
Anophthalmia (Greek: ἀνόφθαλμος, "without eye") is the medical term for the absence of one or both eyes. Both the globe and the ocular tissue are missing from the orbit. The absence of the eye will cause a small bony orbit, a constricte ...
and in rare cases
cyclopia
Cyclopia (named after the Greek mythology characters cyclopes), also known as alobar holoprosencephaly, is the most extreme form of holoprosencephaly and is a congenital disorder (birth defect) characterized by the failure of the embryonic prosen ...
.
It has been shown that the
EVH motifs in the cytoplasmic tail of mouse Fat1 interact with Ena/VASP and ablation of Fat1 by
RNAi
RNA interference (RNAi) is a biological process in which RNA molecules are involved in sequence-specific suppression of gene expression by double-stranded RNA, through translational or transcriptional repression. Historically, RNAi was known b ...
leads to decreased cell migration of rat epithelial cells
The cytoplasmic tail of Fat1 has also been shown to bind the transcriptional repressor
Atrophin in rat vascular smooth muscle cells
At the carboxyl terminus of FAT1 lies a
PDZ domain
The PDZ domain is a common structural domain of 80-90 Amino acid, amino-acids found in the Signal transduction, signaling proteins of bacteria, yeast, plants, viruses and animals. Proteins containing PDZ domains play a key role in anchoring recept ...
(PSD95/Dlg1/ZO-1) ligand motif (-HTEV).
Zebrafish
The zebrafish (''Danio rerio'') is a species of freshwater ray-finned fish belonging to the family Danionidae of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (an ...
Fat1 was found to bind the protein
scribble and regulate Hippo signalling
Using the human
SHSY5Y cell line as a model of neuronal differentiation, human FAT1 was shown to regulate
Hippo
The hippopotamus (''Hippopotamus amphibius;'' ; : hippopotamuses), often shortened to hippo (: hippos), further qualified as the common hippopotamus, Nile hippopotamus and river hippopotamus, is a large semiaquatic Mammal, mammal native to su ...
kinase components with loss of FAT1 leading to nucleocytoplasmic relocation of
TAZ Taz or TAZ may refer to:
Geography
*Taz (river), a river in western Siberia, Russia
*Taz Estuary, the estuary of the river Taz in Russia
People
* Taz people, an ethnic group in Russia
** Taz language, a form of Northeastern Mandarin spoken by ...
and enhanced transcription of the Hippo target gene CTGF. The same study also showed FAT1 was able to regulate
TGF-beta signaling
FAT1 has been found to bind
beta-catenin
Catenin beta-1, also known as β-catenin (''beta''-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene.
β-Catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcrip ...
and regulate
Wnt-signaling in colorectal cancer.
Human FAT1 was found to bind
glypican-3 (GPC3) and regulate cell migration in liver cancer cells.
Structure
The human FAT1 cadherin gene was cloned in 1995 from a human T-leukemia (T-ALL) cell line and consists of 27 exons located on chromosome 4q34–35.
Structurally the FAT1 protein is a single pass transmembrane protein with the extracellular portion consisting of 34 cadherin repeats, 5
EGF-like domains and a
laminin-G like domain.
The FAT1 protein once translated undergoes
furin mediated S1 cleavage forming a non-covalent
heterodimer
In biochemistry, a protein dimer is a macromolecular complex or multimer formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ...
before achieving cell surface expression although this processing is often perturbed in cancer cells which express non-cleaved FAT1 on the cell surface.
FAT1 cadherin is multiply
phosphorylated
In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols:
:
This equation can be writt ...
on its
ectodomain
An ectodomain is the domain of a membrane protein that extends into the extracellular space (the space outside a cell). Ectodomains are usually the parts of proteins that initiate contact with surfaces, which leads to signal transduction. A n ...
but phosphorylation is not catalysed by
FJX1.
The ectodomain of FAT1 can also be shed from the cell surface by the sheddase ADAM10, with release of this ectodomain a possible new
biomarker
In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...
in
pancreatic cancer
Pancreatic cancer arises when cell (biology), cells in the pancreas, a glandular organ behind the stomach, begin to multiply out of control and form a Neoplasm, mass. These cancerous cells have the malignant, ability to invade other parts of ...
.
FAT1 has also been found to undergo
alternative splicing
Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative RNA splicing, splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene ma ...
in breast cancer cells undergoing
epithelial-to-mesenchymal (EMT) transition with the addition of 12 amino acids in the
cytoplasmic
The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell and ...
tail.
Similar splice variants have also been described for murine Fat1 where alternative splicing of the cytoplasmic tail regulated cell migration.
Clinical significance
Cancer
The FAT1 cadherin has been ascribed both as putative tumour suppressor or oncogene in different contexts. Loss of heterozygosity for FAT1 has been reported in primary oral carcinomas
and astrocytic tumours.
There are also reports of over expression of FAT1 in different cancers including DCIS breast cancer,
melanoma,
and leukaemia.
References
Further reading
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{{refend
Biology of bipolar disorder
Tumor suppressor genes