Biology:PLEKHA7

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

PLEKHA7 (Pleckstrin homology domain-containing family A member 7) is an adherens junction (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.[1] It was also independently discovered in Sandra Citi’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.[2]

Structure

The structure of PLEKHA7 is characterized by two WW domains followed by a Pleckstrin homology domain (PH) in the N-terminal region. In the C-terminal half, the protein contains three coiled coil (CC) domains and two Proline-rich (Pro) domains.[2] PLEKHA7 has been detected in different isoforms in a tissue specific manner. Two isoforms 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.[2]

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).[3] 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[4] 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.[2] Cellular localization and tissue distribution of PLEKHA7 has been confirmed by Immunoelectron microscopy (Immuno-EM) of wild type and knock down intestinal epithelial tissues.[2]

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/p120 complex to the minus ends of microtubules (MTs) through Nezha (CAMSAP3).[1] 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.[3] PLEKHA7 knockdown studies in Madin-Darby canine kidney (MDCK) cells indicated its requirement for the AJ localization of paracingulin.[5] Furthermore, the PLEKHA7 homolog in zebrafish, Hadp1, is required for proper heart function and morphogenesis in embryo, regulating the intracellular Ca2+ dynamics through the phosphatidylinositol 4-kinase (PIK4) pathway.[6]

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 instead of sites at basolateral areas of cell–cell contact containing tyrosine-phosphorylated p120 and active Src. Loss of PLEKHA7 disrupts miRNAs regulation, causing tumorigenic signaling and growth. Restoring normal miRNA levels in tumor cells can reverse that aberrant signaling.[7][8][9] In 2015 it was also discovered that PLEKHA7 has a role in controlling susceptibility to Staphylococcus aureus alpha-toxin [10] 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.[10]

In 2016, researchers found that PLEKHA7 recruits the small PDZ protein PDZD11 to adherens junctions, thus resulting in the stabilisation of nectins at adherens junctions.[11] Knock-out of PLEKHA7 results in the loss of PDZD11 from epithelial adherens junctions, and this is rescued by the introduction of exogenous PLEKHA7.[11] The N-terminal 44 residues of PDZD11 interact with the first WW domain of PLEKHA7.[11] 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.[11] PDZD11 interacts directly with the cytoplasmic PDZ-binding motif of nectins, through its own PDZ domain.[11] Proximity ligation assay shows that PLEKHA7 is associated to nectins in a PDZD11-dependent manner.[11] Nectins are the second major class of transmembrane adhesion molecules at adherens junctions, besides cadherins. Therefore, PLEKHA7 stabilises both cadherins and nectins at AJ.[11]

Clinical significance

Genome-wide association studies suggest that PLEKHA7 is associated with blood pressure and hypertension[12] [13] [14] [15] and primary angle closure glaucoma.[16] [17] [18] [19] [20] [21] [22] Also, an increased expression of PLEKHA7 in invasive lobular breast cancer has been reported.[23] 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 [24] 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.[7]

References

  1. ↑ 1.0 1.1 "Anchorage of microtubule minus ends to adherens junctions regulates epithelial cell-cell contacts". Cell 135 (5): 948–59. November 2008. doi:10.1016/j.cell.2008.09.040. PMID 19041755. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 "PLEKHA7 is an adherens junction protein with a tissue distribution and subcellular localization distinct from ZO-1 and E-cadherin". PLOS ONE 5 (8): e12207. August 2010. doi:10.1371/journal.pone.0012207. PMID 20808826. Bibcode: 2010PLoSO...512207P. 
  3. ↑ 3.0 3.1 "Binding between the junctional proteins afadin and PLEKHA7 and implication in the formation of adherens junction in epithelial cells". The Journal of Biological Chemistry 288 (41): 29356–68. October 2013. doi:10.1074/jbc.M113.453464. PMID 23990464. 
  4. ↑ "PLEKHA7 Recruits PDZD11 to Adherens Junctions to Stabilize Nectins". The Journal of Biological Chemistry 291 (21): 11016–29. May 2016. doi:10.1074/jbc.M115.712935. PMID 27044745. 
  5. ↑ "A role for ZO-1 and PLEKHA7 in recruiting paracingulin to tight and adherens junctions of epithelial cells". The Journal of Biological Chemistry 286 (19): 16743–50. May 2011. doi:10.1074/jbc.M111.230862. PMID 21454477. 
  6. ↑ "Hadp1, a newly identified pleckstrin homology domain protein, is required for cardiac contractility in zebrafish". Disease Models & Mechanisms 4 (5): 607–21. September 2011. doi:10.1242/dmm.002204. PMID 21628396. 
  7. ↑ 7.0 7.1 "Distinct E-cadherin-based complexes regulate cell behaviour through miRNA processing or Src and p120 catenin activity". Nature Cell Biology 17 (9): 1145–57. September 2015. doi:10.1038/ncb3227. PMID 26302406. 
  8. ↑ "Mayo Clinic researchers find new code that makes reprogramming of cancer cells possible". 24 August 2015. http://newsnetwork.mayoclinic.org/discussion/mayo-clinic-researchers-find-new-code-that-makes-reprogramming-of-cancer-cells-possible/. 
  9. ↑ Distinct E-cadherin-based complexes regulate cell behaviour through miRNA processing or Src and p120 catenin activity. Kourtidis et al. 2015
  10. ↑ 10.0 10.1 "The adherens junctions control susceptibility to Staphylococcus aureus α-toxin". Proceedings of the National Academy of Sciences of the United States of America 112 (46): 14337–42. November 2015. doi:10.1073/pnas.1510265112. PMID 26489655. Bibcode: 2015PNAS..11214337P. 
  11. ↑ 11.0 11.1 11.2 11.3 11.4 11.5 11.6 http://www.jbc.org/content/early/2016/04/04/jbc.M115.712935.full.pdf [|permanent dead link|dead link}}]
  12. ↑ "Recapitulation of two genomewide association studies on blood pressure and essential hypertension in the Korean population". Journal of Human Genetics 55 (6): 336–41. June 2010. doi:10.1038/jhg.2010.31. PMID 20414254. 
  13. ↑ "Genetic variations in the CYP17A1 and NT5C2 genes are associated with a reduction in visceral and subcutaneous fat areas in Japanese women". Journal of Human Genetics 57 (1): 46–51. January 2012. doi:10.1038/jhg.2011.127. PMID 22071413. 
  14. ↑ "Genome-wide association study of blood pressure and hypertension". Nature Genetics 41 (6): 677–87. June 2009. doi:10.1038/ng.384. PMID 19430479. 
  15. ↑ "Genetic variations in CYP17A1, CACNB2 and PLEKHA7 are associated with blood pressure and/or hypertension in She ethnic minority of China". Atherosclerosis 219 (2): 709–14. December 2011. doi:10.1016/j.atherosclerosis.2011.09.006. PMID 21963141. 
  16. ↑ "Association of genetic variants with primary angle closure glaucoma in two different populations". PLOS ONE 8 (6): e67903. Jun 2013. doi:10.1371/journal.pone.0067903. PMID 23840785. Bibcode: 2013PLoSO...867903A. 
  17. ↑ "Genotype-phenotype analysis of SNPs associated with primary angle closure glaucoma (rs1015213, rs3753841 and rs11024102) and ocular biometry in the EPIC-Norfolk Eye Study". The British Journal of Ophthalmology 97 (6): 704–7. June 2013. doi:10.1136/bjophthalmol-2012-302969. PMID 23505305. 
  18. ↑ "Association study in a South Indian population supports rs1015213 as a risk factor for primary angle closure". Investigative Ophthalmology & Visual Science 54 (8): 5624–8. August 2013. doi:10.1167/iovs.13-12186. PMID 23847314. 
  19. ↑ "Lack of association between primary angle-closure glaucoma susceptibility loci and the ocular biometric parameters anterior chamber depth and axial length". Investigative Ophthalmology & Visual Science 54 (8): 5824–8. August 2013. doi:10.1167/iovs.13-11901. PMID 23920366. 
  20. ↑ "Genotype-phenotype correlation analysis for three primary angle closure glaucoma-associated genetic polymorphisms". Investigative Ophthalmology & Visual Science 55 (2): 1143–8. February 2014. doi:10.1167/iovs.13-13552. PMID 24474268. 
  21. ↑ "Genome-wide association analyses identify three new susceptibility loci for primary angle closure glaucoma". Nature Genetics 44 (10): 1142–1146. October 2012. doi:10.1038/ng.2390. PMID 22922875. 
  22. ↑ "An extensive replication study on three new susceptibility Loci of primary angle closure glaucoma in han chinese: jiangsu eye study". Journal of Ophthalmology 2013: 641596. Jan 2013. doi:10.1155/2013/641596. PMID 24282630. 
  23. ↑ "Genetic up-regulation and overexpression of PLEKHA7 differentiates invasive lobular carcinomas from invasive ductal carcinomas". Human Pathology 43 (11): 1902–9. November 2012. doi:10.1016/j.humpath.2012.01.017. PMID 22542108. 
  24. ↑ "The Expression of the Zonula Adhaerens Protein PLEKHA7 Is Strongly Decreased in High Grade Ductal and Lobular Breast Carcinomas". PLOS ONE 10 (8): e0135442. 2015-01-01. doi:10.1371/journal.pone.0135442. PMID 26270346. Bibcode: 2015PLoSO..1035442T. 



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