PLEKHA7 explained

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

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.[10] Knock-out of PLEKHA7 results in the loss of PDZD11 from epithelial adherens junctions, and this is rescued by the introduction of exogenous PLEKHA7.[10] The N-terminal 44 residues of PDZD11 interact with the first WW domain of PLEKHA7.[10] 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.[10] PDZD11 interacts directly with the cytoplasmic PDZ-binding motif of nectins, through its own PDZ domain.[10] Proximity ligation assay shows that PLEKHA7 is associated to nectins in a PDZD11-dependent manner.[10] Nectins are the second major class of transmembrane adhesion molecules at adherens junctions, besides cadherins. Therefore, PLEKHA7 stabilises both cadherins and nectins at AJ.[10]

Clinical significance

Genome-wide association studies suggest that PLEKHA7 is associated with blood pressure and hypertension[11] [12] [13] [14] and primary angle closure glaucoma.[15] [16] [17] [18] [19] [20] [21] Also, an increased expression of PLEKHA7 in invasive lobular breast cancer has been reported.[22] 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 [23] 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.[24]

Notes and References

  1. Meng W, Mushika Y, Ichii T, Takeichi M . Anchorage of microtubule minus ends to adherens junctions regulates epithelial cell-cell contacts . Cell . 135 . 5 . 948–59 . November 2008 . 19041755 . 10.1016/j.cell.2008.09.040 . 14503414 . free .
  2. Pulimeno P, Bauer C, Stutz J, Citi S . 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 . 20808826 . 2924883 . 10.1371/journal.pone.0012207 . 2010PLoSO...512207P . free .
  3. Kurita S, Yamada T, Rikitsu E, Ikeda W, Takai Y . 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 . 23990464 . 3795237 . 10.1074/jbc.M113.453464 . free .
  4. Guerrera D, Shah J, Vasileva E, Sluysmans S, Méan I, Jond L, Poser I, Mann M, Hyman AA, Citi S . PLEKHA7 Recruits PDZD11 to Adherens Junctions to Stabilize Nectins . The Journal of Biological Chemistry . 291 . 21 . 11016–29 . May 2016 . 27044745 . 4900252 . 10.1074/jbc.M115.712935 . free .
  5. Pulimeno P, Paschoud S, Citi S . 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 . 21454477 . 3089516 . 10.1074/jbc.M111.230862 . free .
  6. Wythe JD, Jurynec MJ, Urness LD, Jones CA, Sabeh MK, Werdich AA, Sato M, Yost HJ, Grunwald DJ, Macrae CA, Li DY . Hadp1, a newly identified pleckstrin homology domain protein, is required for cardiac contractility in zebrafish . Disease Models & Mechanisms . 4 . 5 . 607–21 . September 2011 . 21628396 . 3180224 . 10.1242/dmm.002204 .
  7. Web site: Mayo Clinic researchers find new code that makes reprogramming of cancer cells possible. 24 August 2015 .
  8. http://www.nature.com/ncb/journal/vaop/ncurrent/full/ncb3227.html Distinct E-cadherin-based complexes regulate cell behaviour through miRNA processing or Src and p120 catenin activity. Kourtidis et al. 2015
  9. Popov LM, Marceau CD, Starkl PM, Lumb JH, Shah J, Guerrera D, Cooper RL, Merakou C, Bouley DM, Meng W, Kiyonari H, Takeichi M, Galli SJ, Bagnoli F, Citi S, Carette JE, Amieva MR . 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 . 26489655 . 4655540 . 10.1073/pnas.1510265112 . 2015PNAS..11214337P . free .
  10. http://www.jbc.org/content/early/2016/04/04/jbc.M115.712935.full.pdf
  11. Hong KW, Jin HS, Lim JE, Kim S, Go MJ, Oh B . 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 . 20414254 . 10.1038/jhg.2010.31 . free .
  12. Hotta K, Kitamoto A, Kitamoto T, Mizusawa S, Teranishi H, Matsuo T, Nakata Y, Hyogo H, Ochi H, Nakamura T, Kamohara S, Miyatake N, Kotani K, Komatsu R, Itoh N, Mineo I, Wada J, Yoneda M, Nakajima A, Funahashi T, Miyazaki S, Tokunaga K, Masuzaki H, Ueno T, Chayama K, Hamaguchi K, Yamada K, Hanafusa T, Oikawa S, Yoshimatsu H, Sakata T, Tanaka K, Matsuzawa Y, Nakao K, Sekine A . 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 . 22071413 . 10.1038/jhg.2011.127 . free . 2433/189865 . free .
  13. Levy D, Ehret GB, Rice K, Verwoert GC, Launer LJ, Dehghan A, Glazer NL, Morrison AC, Johnson AD, Aspelund T, Aulchenko Y, Lumley T, Köttgen A, Vasan RS, Rivadeneira F, Eiriksdottir G, Guo X, Arking DE, Mitchell GF, Mattace-Raso FU, Smith AV, Taylor K, Scharpf RB, Hwang SJ, Sijbrands EJ, Bis J, Harris TB, Ganesh SK, O'Donnell CJ, Hofman A, Rotter JI, Coresh J, Benjamin EJ, Uitterlinden AG, Heiss G, Fox CS, Witteman JC, Boerwinkle E, Wang TJ, Gudnason V, Larson MG, Chakravarti A, Psaty BM, van Duijn CM . Genome-wide association study of blood pressure and hypertension . Nature Genetics . 41 . 6 . 677–87 . June 2009 . 19430479 . 2998712 . 10.1038/ng.384 .
  14. Lin Y, Lai X, Chen B, Xu Y, Huang B, Chen Z, Zhu S, Yao J, Jiang Q, Huang H, Wen J, Chen G . 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 . 21963141 . 10.1016/j.atherosclerosis.2011.09.006 .
  15. Awadalla MS, Thapa SS, Hewitt AW, Burdon KP, Craig JE . Association of genetic variants with primary angle closure glaucoma in two different populations . PLOS ONE . 8 . 6 . e67903 . Jun 2013 . 23840785 . 3695871 . 10.1371/journal.pone.0067903 . 2013PLoSO...867903A . free .
  16. Day AC, Luben R, Khawaja AP, Low S, Hayat S, Dalzell N, Wareham NJ, Khaw KT, Foster PJ . 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 . 23505305 . 4624259 . 10.1136/bjophthalmol-2012-302969 .
  17. Duvesh R, Verma A, Venkatesh R, Kavitha S, Ramulu PY, Wojciechowski R, Sundaresan P . 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 . 23847314 . 3747718 . 10.1167/iovs.13-12186 .
  18. 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 . 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 . 23920366 . 10.1167/iovs.13-11901 . free .
  19. Wei X, Nongpiur ME, de Leon MS, Baskaran M, Perera SA, How AC, Vithana EN, Khor CC, Aung T . Genotype-phenotype correlation analysis for three primary angle closure glaucoma-associated genetic polymorphisms . Investigative Ophthalmology & Visual Science . 55 . 2 . 1143–8 . February 2014 . 24474268 . 10.1167/iovs.13-13552 .
  20. Vithana EN, Khor CC, Qiao C, Nongpiur ME, George R, Chen LJ, Do T, Abu-Amero K, Huang CK, Low S, Tajudin LA, Perera SA, Cheng CY, Xu L, Jia H, Ho CL, Sim KS, Wu RY, Tham CC, Chew PT, Su DH, Oen FT, Sarangapani S, Soumittra N, Osman EA, Wong HT, Tang G, Fan S, Meng H, Huong DT, Wang H, Feng B, Baskaran M, Shantha B, Ramprasad VL, Kumaramanickavel G, Iyengar SK, How AC, Lee KY, Sivakumaran TA, Yong VH, Ting SM, Li Y, Wang YX, Tay WT, Sim X, Lavanya R, Cornes BK, Zheng YF, Wong TT, Loon SC, Yong VK, Waseem N, Yaakub A, Chia KS, Allingham RR, Hauser MA, Lam DS, Hibberd ML, Bhattacharya SS, Zhang M, Teo YY, Tan DT, Jonas JB, Tai ES, Saw SM, Hon DN, Al-Obeidan SA, Liu J, Chau TN, Simmons CP, Bei JX, Zeng YX, Foster PJ, Vijaya L, Wong TY, Pang CP, Wang N, Aung T . Genome-wide association analyses identify three new susceptibility loci for primary angle closure glaucoma . Nature Genetics . 44 . 10 . 1142–1146 . October 2012 . 22922875 . 4333205 . 10.1038/ng.2390 .
  21. Shi H, Zhu R, Hu N, Shi J, Zhang J, Jiang L, Jiang H, Guan H . 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 . 24282630 . 3824414 . 10.1155/2013/641596 . free .
  22. Castellana B, Escuin D, Pérez-Olabarria M, Vázquez T, Muñoz J, Peiró G, Barnadas A, Lerma E . Genetic up-regulation and overexpression of PLEKHA7 differentiates invasive lobular carcinomas from invasive ductal carcinomas . Human Pathology . 43 . 11 . 1902–9 . November 2012 . 22542108 . 10.1016/j.humpath.2012.01.017 .
  23. Tille JC, Ho L, Shah J, Seyde O, McKee TA, Citi S . 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 . 26270346 . 4535953 . 10.1371/journal.pone.0135442 . 2015PLoSO..1035442T . free .
  24. Kourtidis A, Ngok SP, Pulimeno P, Feathers RW, Carpio LR, Baker TR, Carr JM, Yan IK, Borges S, Perez EA, Storz P, Copland JA, Patel T, Thompson EA, Citi S, Anastasiadis PZ . 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 . 26302406 . 4975377 . 10.1038/ncb3227.

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