PLEKHA7

PLEKHA7 (pleckstrin homology domain containing, family A member 7)
Identifiers
Symbols PLEKHA7 ; DKFZp686M22243
External IDs OMIM: 612686 MGI: 2445094 HomoloGene: 52172 GeneCards: PLEKHA7 Gene
Orthologs
Species Human Mouse
Entrez 144100 233765
Ensembl ENSG00000166689 ENSMUSG00000045659
UniProt Q61Q23 Q3UIL6
RefSeq (mRNA) NM_175058.4 NM_172743.2
RefSeq (protein) NP_778228.3 NP_766331.1
Location (UCSC) Chr 11:
16.81 – 16.84 Mb		 Chr 7:
4123.27 – 123.38 Mb
PubMed search

PLEKHA7 (Pleckstrin homology domain-containing family A member 7) is an adherens junction (AJ) protein, discovered in Masatoshi Takeichi’s lab while looking for potential binding partners for the N-terminal region of p120-catenin. 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] PLEKHA7 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 p120Catenin (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.[5] 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.[6] 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.[7]

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.[8][9][10] In 2015 it was also discovered that PLEKHA7 has a role in controlling susceptibility to Staphylococcus aureus alpha-toxin [11] 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.[11]

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[12]. Knock-out of PLEKHA7 results in the loss of PDZD11 from epithelial adherens junctions, and this is rescued by the introduction of exogenous PLEKHA7[13]. The N-terminal 44 residues of PDZD11 interact with the first WW domain of PLEKHA7[14]. 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[15]. PDZD11 interacts directly with the cytoplasmic PDZ-binding motif of nectins, through its own PDZ domain[16]. Proximity ligation assay shows that PLEKHA7 is associated to nectins in a PDZD11-dependent manner[17]. Nectins are the second major class of transmembrane adhesion molecules at adherens junctions, besides cadherins. Therefore PLEKHA7lstabilises both cadherins and nectins at AJ[18].

Clinical significance

Genome-wide association studies suggest that PLEKHA7 is associated with blood pressure and hypertension[19] [20] [21] [22] and primary angle closure glaucoma.[23] [24] [25] [26] [27] [28] [29] Also, an increased expression of PLEKHA7 in invasive lobular breast cancer has been reported.[30] 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 [31]. 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.[32]

References

  1. 1 2 Meng W, Mushika Y, Ichii T, Takeichi M. (Nov 2008). "Anchorage of microtubule minus ends to adherens junctions regulates epithelial cell-cell contacts.". Cell 135 (5): 948–59. doi:10.1016/j.cell.2008.09.040. PMID 19041755.
  2. 1 2 3 4 Pulimeno P, Bauer C, Stutz J, Citi S. (Aug 2010). "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. doi:10.1371/journal.pone.0012207. PMC 2924883. PMID 20808826.
  3. 1 2 Kurita S, Yamada T, Rikitsu E, Ikeda W, Takai Y (Oct 2013). "Binding between the junctional proteins afadin and PLEKHA7 and implication in the formation of adherens junction in epithelial cells". J Biol Chem 288 (41): 29356–68. doi:10.1074/jbc.M113.453464. PMID 23990464.
  4. ↑ http://www.ncbi.nlm.nih.gov/pubmed/27044745
  5. ↑ Pulimeno, Pamela; Bauer, Christoph; Stutz, Jeffrey; Citi, Sandra (2010-01-01). "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. doi:10.1371/journal.pone.0012207. ISSN 1932-6203. PMC 2924883. PMID 20808826.
  6. ↑ Pulimeno P, Paschoud S, Citi S. (May 2011). "A role for ZO-1 and PLEKHA7 in recruiting paracingulin to tight and adherens junctions of epithelial cells.". J. Biol. Chem. 286 (19): 16743–50. doi:10.1074/jbc.M111.230862. PMC 3089516. PMID 21454477.
  7. ↑ Wythe JD, Jurynec MJ, Urness LD, Jones CA, Sabeh MK, Werdich AA, Sato M, Yost HJ, Grunwald DJ, Macrae CA, Li DY. (Sep 2011). "Hadp1, a newly identified pleckstrin homology domain protein, is required for cardiac contractility in zebrafish.". Dis Model Mech. 4 (5): 607–21. doi:10.1242/dmm.002204. PMC 3180224. PMID 21628396.
  8. ↑ "Distinct E-cadherin-based complexes regulate cell behaviour through miRNA processing or Src and p120 catenin activity". Nature Cell Biology 17: 1145–1157. 24 August 2015. doi:10.1038/ncb3227.
  9. ↑ "Mayo Clinic researchers find new code that makes reprogramming of cancer cells possible".
  10. ↑ Distinct E-cadherin-based complexes regulate cell behaviour through miRNA processing or Src and p120 catenin activity. Kourtidis et al. 2015
  11. 1 2 Popov, Lauren M.; Marceau, Caleb D.; Starkl, Philipp M.; Lumb, Jennifer H.; Shah, Jimit; Guerrera, Diego; Cooper, Rachel L.; Merakou, Christina; Bouley, Donna M. (2015-10-21). "The adherens junctions control susceptibility to Staphylococcus aureus α-toxin". Proceedings of the National Academy of Sciences of the United States of America 112: 14337–42. doi:10.1073/pnas.1510265112. ISSN 1091-6490. PMID 26489655.
  12. ↑ http://www.jbc.org/content/early/2016/04/04/jbc.M115.712935.full.pdf
  13. ↑ http://www.jbc.org/content/early/2016/04/04/jbc.M115.712935.full.pdf
  14. ↑ http://www.jbc.org/content/early/2016/04/04/jbc.M115.712935.full.pdf
  15. ↑ http://www.jbc.org/content/early/2016/04/04/jbc.M115.712935.full.pdf
  16. ↑ http://www.jbc.org/content/early/2016/04/04/jbc.M115.712935.full.pdf
  17. ↑ http://www.jbc.org/content/early/2016/04/04/jbc.M115.712935.full.pdf
  18. ↑ http://www.jbc.org/content/early/2016/04/04/jbc.M115.712935.full.pdf
  19. ↑ Hong KW, Jin HS, Lim JE, Kim S, Go MJ, Oh B. (Jun 2010). "Recapitulation of two genomewide association studies on blood pressure and essential hypertension in the Korean population.". J Hum Genet. 55 (6): 336–41. doi:10.1038/jhg.2010.31. PMID 20414254.
  20. ↑ Hotta; et al. (Jan 2012). "Genetic variations in the CYP17A1 and NT5C2 genes are associated with a reduction in visceral and subcutaneous fat areas in Japanese women.". J Hum Genet. 57 (1): 46–51. doi:10.1038/jhg.2011.127. PMID 22071413.
  21. ↑ Levy; et al. (Jun 2009). "Genome-wide association study of blood pressure and hypertension.". Nat. Genet. 41 (6): 677–87. doi:10.1038/ng.384. PMC 2998712. PMID 19430479.
  22. ↑ Lin Y, Lai X, Chen B, Xu Y, Huang B, Chen Z, Zhu S, Yao J, Jiang Q, Huang H, Wen J, Chen G. (Dec 2011). "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. doi:10.1016/j.atherosclerosis.2011.09.006. PMID 21963141.
  23. ↑ Awadalla MS, Thapa SS, Hewitt AW, Burdon KP, Craig JE. (Jun 2013). "Association of genetic variants with primary angle closure glaucoma in two different populations.". PLOS ONE 8 (6): e67903. doi:10.1371/journal.pone.0067903. PMC 3695871. PMID 23840785.
  24. ↑ Day AC, Luben R, Khawaja AP, Low S, Hayat S, Dalzell N, Wareham NJ, Khaw KT, Foster PJ. (Jun 2013). "Genotype-phenotype analysis of SNPs associated with primary angle closure glaucoma (rs1015213, rs3753841 and rs11024102) and ocular biometry in the EPIC-Norfolk Eye Study.". Br J Ophthalmol. 97 (6): 704–7. doi:10.1136/bjophthalmol-2012-302969. PMID 23505305.
  25. ↑ Duvesh R, Verma A, Venkatesh R, Kavitha S, Ramulu PY, Wojciechowski R, Sundaresan P. (Aug 2013). "Association study in a South Indian population supports rs1015213 as a risk factor for primary angle closure.". Invest Ophthalmol Vis Sci. 54 (8): 5624–8. doi:10.1167/iovs.13-12186. PMC 3747718. PMID 23847314.
  26. ↑ Nongpiur ME, Wei X, Xu L, Perera SA, Wu RY, Zheng Y, Li Y, Wang YX, Cheng CY, Jonas JB, Wong TY, Vithana EN, Aung T, Khor CC (Aug 2013). "Lack of association between primary angle-closure glaucoma susceptibility loci and the ocular biometric parameters anterior chamber depth and axial length.". Invest Ophthalmol Vis Sci 54 (8): 5824–8. doi:10.1167/iovs.13-11901. PMID 23920366.
  27. ↑ Wei X, Nongpiur ME, De Leon JM, Baskaran M, Perera SA, How AC, Vithana EN, Khor CC, Aung T. (Jan 2014). "Genotype-Phenotype Correlation Analysis for Three Primary Angle Closure Glaucoma Associated Genetic Polymorphisms.". Invest Ophthalmol Vis Sci 55 (2): 1143–8. doi:10.1167/iovs.13-13552. PMID 24474268.
  28. ↑ Vithana; et al. (Oct 2012). "Genome-wide association analyses identify three new susceptibility loci for primary angle closure glaucoma.". Nat. Genet. 44 (10): 1142–6. doi:10.1038/ng.2390. PMID 22922875.
  29. ↑ Shi H, Zhu R, Hu N, Shi J, Zhang J, Jiang L, Jiang H, Guan H. (Jan 2013). "An extensive replication study on three new susceptibility Loci of primary angle closure glaucoma in han Chinese: jiangsu eye study.". J Ophthalmol. 641596: 641596. doi:10.1155/2013/641596. PMC 3824414. PMID 24282630.
  30. ↑ Castellana B, Escuin D, Pérez-Olabarria M, Vázquez T, Muñoz J, Peiró G, Barnadas A, Lerma E. (Nov 2012). "Genetic up-regulation and overexpression of PLEKHA7 differentiates invasive lobular carcinomas from invasive ductal carcinomas.". Hum Pathol. 43 (11): 1902–9. doi:10.1016/j.humpath.2012.01.017. PMID 22542108.
  31. ↑ Tille, Jean-Christophe; Ho, Liza; Shah, Jimit; Seyde, Olivia; McKee, Thomas A.; Citi, Sandra (2015-01-01). "The Expression of the Zonula Adhaerens Protein PLEKHA7 Is Strongly Decreased in High Grade Ductal and Lobular Breast Carcinomas". PLOS ONE 10 (8): e0135442. doi:10.1371/journal.pone.0135442. ISSN 1932-6203. PMC 4535953. PMID 26270346.
  32. ↑ Antonis Kourtidis, Siu P. Ngok, Pamela Pulimeno, Ryan W. Feathers, Lomeli R. Carpio, Tiffany R. Baker, Jennifer M. Carr, Irene K. Yan, Sahra Borges, Edith A. Perez, Peter Storz, John A. Copland, Tushar Patel, E. Aubrey Thompson, Sandra Citi, Panos Z. Anastasiadis (24 August 2015). "Distinct E-cadherin-based complexes regulate cell behaviour through miRNA processing or Src and p120 catenin activity". Nature Cell Biology 17: 1145–1157. doi:10.1038/ncb3227. horizontal tab character in |author= at position 32 (help)
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