PLEKHA7
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PLEKHA7 (Pleckstrin homology domain-containing family A member 7) is an
adherens junction In cell biology, adherens junctions (or zonula adherens, intermediate junction, or "belt desmosome") are protein complexes that occur at cell–cell junctions and cell–matrix junctions in epithelial and endothelial tissues, usually more basa ...
(AJ) protein, involved in the junction's integrity and stability.


History

The protein was discovered in Masatoshi Takeichi’s lab while looking for potential binding partners for the N-terminal region of p120. PLEKHA7 was identified by mass spectrometry in lysates of human intestinal carcinoma ( Caco-2) cells in a GST-pull down using N-terminal GST- fusion p120 catenin as bait. It was also independently discovered in
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’s group as a protein interacting with globular head domain of the Paracingulin in a yeast two-hybrid screen. PLEKHA7 localizes at epithelial zonular AJs.


Structure

The structure of PLEKHA7 is characterized by two
WW domain The WW domain (also known as the rsp5-domain or WWP repeating structural motif, motif) is a modular protein domain that mediates specific interactions with protein ligands. This domain is found in a number of unrelated signaling and structural pro ...
s followed by a
Pleckstrin homology domain Pleckstrin homology domain (PH domain) or (PHIP) is a protein domain of approximately 120 amino acids that occurs in a wide range of proteins involved in intracellular signaling or as constituents of the cytoskeleton. This domain can bind phosph ...
(PH) in the N-terminal region. In the C-terminal half, the protein contains three
coiled coil A coiled coil is a structural motif in proteins in which two to seven alpha-helices are coiled together like the strands of a rope. ( Dimers and trimers are the most common types.) They have been found in roughly 5-10% of proteins and have a ...
(CC) domains and two Proline-rich (Pro) domains. PLEKHA7 has been detected in different isoforms in a tissue specific manner. Two
isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...
s of 135 kDa and 145 kDa have been reported in colon, liver, lung, eye, pancreas, kidney and heart. Additionally, two major transcripts of 5.5 kb and 6.5 kb have been identified in brain, kidney, liver, small intestine, placenta and lung, while only one PLEKHA7 mRNA transcript of 5.5 kb is identified in heart, brain, colon and skeletal muscle.


Protein-protein interactions

In vitro interaction studies were pursued to map the interaction(s) of PLEKHA7 with p120 (residues 538-696), Nezha ( CAMSAP3) (residues 680-821), paracingulin (residues 620-769) and Afadin (residues 120-374). The protein PDZD11 was identified as a protein interacting through its N-terminal region with the N-terminal WW domain of PLEKHA7, based on 2-hybrid screen and analysis of PLEKHA7 immunoprecipitates Unlike most other AJ proteins, but similar to afadin, PLEKHA7 is exclusively detected in the zonular apical part of AJ, but not in the “puncta adherentia” along lateral membranes of the epithelial cells. Cellular localization and tissue distribution of PLEKHA7 has been confirmed by Immunoelectron microscopy (Immuno-EM) of wild type and knock down intestinal epithelial tissues.


Function

The first identified function of PLEKHA7 was is to contribute to integrity and stability of the zonula adherens junctions by linking the
E-cadherin Cadherin-1 or Epithelial cadherin (E-cadherin), is a protein that in humans is encoded by the ''CDH1'' gene (not to be confused with the APC/C activator protein CDH1). Mutations are correlated with Hereditary diffuse gastric cancer, gastric, Here ...
/p120 complex to the minus ends of
microtubules Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27  nm and have an inner diameter between 11 an ...
(MTs) through Nezha (CAMSAP3). The PLEKHA7-Nezha- MTs complex allows transport of the KIFC3 (a minus end directed motor) to the AJ. However, in Eph4 cell line, PLEKHA7 is recruited to E-cadherin based AJ by Afadin, independently of p120. PLEKHA7 knockdown studies in Madin-Darby canine kidney (
MDCK Madin-Darby canine kidney (MDCK) cells are a model mammalian cell line used in biomedical research. MDCK cells are used for a wide variety of cell biology studies including cell polarity, cell-cell adhesions (termed adherens junctions), collectiv ...
) cells indicated its requirement for the AJ localization of paracingulin. Furthermore, the PLEKHA7 homolog in
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 ...
, Hadp1, is required for proper heart function and
morphogenesis Morphogenesis (from the Greek ''morphê'' shape and ''genesis'' creation, literally "the generation of form") is the biological process that causes a cell, tissue or organism to develop its shape. It is one of three fundamental aspects of deve ...
in embryo, regulating the intracellular dynamics through the phosphatidylinositol 4-kinase (PIK4) pathway. In 2015, researchers discovered that PLEKHA7 recruits the so-called microprocessor complex (association of Drosha and DGCR8 proteins) to a growth-inhibiting site (apical zonula adherens) in
epithelial cells 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 man ...
instead of sites at basolateral areas of cell–cell contact containing
tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a conditionally essential amino acid with a polar side group. The word "tyrosine" is ...
-
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 ...
p120 and active Src. Loss of PLEKHA7 disrupts
miRNA Micro ribonucleic acid (microRNA, miRNA, μRNA) are small, single-stranded, non-coding RNA molecules containing 21–23 nucleotides. Found in plants, animals, and even some viruses, miRNAs are involved in RNA silencing and post-transcri ...
s regulation, causing tumorigenic signaling and growth. Restoring normal miRNA levels in tumor cells can reverse that aberrant signaling. In 2015 it was also discovered that PLEKHA7 has a role in controlling susceptibility to Staphylococcus aureus alpha-toxin Cells lacking PLEKHA7 are injured by the toxin, but recover after intoxication. Mice knockout for PLEKHA7 are viable and fertile, and when infected with methycillin-resistant S. aureus USA300 LAC strain they show a decreased disease severity in both skin infection and lethal pneumonia, thus identifying PLEKHA7 as a potential nonessential host target to reduce S. aureus virulence during epithelial infections. In 2016, researchers found that PLEKHA7 recruits the small PDZ protein
PDZD11 PDZ domain-containing protein 11 is a protein that in humans is encoded by the ''PDZD11'' 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 DN ...
to adherens junctions, thus resulting in the stabilisation of nectins at adherens junctions.http://www.jbc.org/content/early/2016/04/04/jbc.M115.712935.full.pdf Knock-out of PLEKHA7 results in the loss of PDZD11 from epithelial adherens junctions, and this is rescued by the introduction of exogenous PLEKHA7. The N-terminal 44 residues of PDZD11 interact with the first WW domain of PLEKHA7. In the absence of either PLEKHA7 or PDZD11, the amount of nectin-3 and nectin-4 detected at junctions is decreased, as well as total nectin levels, through proteasome-mediated degradation. PDZD11 interacts directly with the cytoplasmic PDZ-binding motif of nectins, through its own PDZ domain.
Proximity ligation assay Proximity ligation assay (in situ PLA) is a technology that extends the capabilities of traditional immunoassays to include direct detection of proteins, protein interaction, protein interactions, extracellular vesicles and post translational modi ...
shows that PLEKHA7 is associated to nectins in a PDZD11-dependent manner. Nectins are the second major class of transmembrane adhesion molecules at adherens junctions, besides cadherins. Therefore, PLEKHA7 stabilises both cadherins and nectins at AJ.


Clinical significance

Genome-wide association studies In genomics, a genome-wide association study (GWA study, or GWAS), is an observational study of a genome-wide set of genetic variants in different individuals to see if any variant is associated with a trait. GWA studies typically focus on assoc ...
suggest that PLEKHA7 is associated with
blood pressure Blood pressure (BP) is the pressure of Circulatory system, circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term ...
and hypertension and primary angle closure
glaucoma Glaucoma is a group of eye diseases that can lead to damage of the optic nerve. The optic nerve transmits visual information from the eye to the brain. Glaucoma may cause vision loss if left untreated. It has been called the "silent thief of ...
. Also, an increased expression of PLEKHA7 in invasive lobular
breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...
has been reported. In a more recent study, the expression of PLEKHA7 protein in high grade ductal breast carcinomas, and lobular breast carcinomas was found to be very low or undetectable by immunofluorescence or immunohistochemistry, despite the detection of PLEKHA7 mRNA A Mayo Clinic study published online in August 2015 found that PLEKHA7 is mis-localized or lost in almost all breast and kidney tumor patient samples examined.


References

{{Cytoskeletal proteins Cell adhesion proteins Transmembrane proteins