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'''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 p-120 Catenin. PLEKHA7 was identified by mass spectrometry in lysates of human intestinal carcinoma (Caco2) cells in a GST-pull down using N-terminal GST-fusion p-120 catenin as bait.<ref>[10]</ref>
'''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 p-120 [[Catenin]]. PLEKHA7 was identified by mass spectrometry in [[lysate]]s of human intestinal carcinoma (Caco2) cells in a GST-pull down using N-terminal GST-fusion p-120 catenin as bait.
⚫
<ref name="pmid19041755">{{cite journal | title=Anchorage of microtubule minus ends to adherens junctions regulates epithelial cell-cell contacts. | author=Meng W, Mushika Y, Ichii T, Takeichi M. | journal=Cell | year=2008 | month=Nov | volume=135 | issue=5 | pages=948-59 | doi=10.1016/j.cell.2008.09.040 | PMID=19041755}}</ref>
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<ref>[12]</ref>
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.<ref name="pmid20808826">{{cite journal | title=PLEKHA7 is an adherens junction protein with a tissue distribution and subcellular localization distinct from ZO-1 and E-cadherin. | author=Pulimeno P, Bauer C, Stutz J, Citi S. | journal=PLoS One | year=2010 | month=Aug | volume=5 | issue=8 | pages=e12207 | doi=10.1371/journal.pone.0012207 | PMID=20808826}}</ref>


== Structure ==
== 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 (Figure 1).<ref>[12]</ref>
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.<ref name="pmid20808826"/>
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.<ref>[12]</ref>
PLEKHA7 has been detected in different isoforms in a tissue specific manner. Two [[isoform]]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.<ref name="pmid20808826"/>


== Protein-protein Interactions ==
== Protein-protein Interactions ==


In vitro interaction studies were pursued to map the interaction(s) of PLEKHA 7 with p-120 Catenin (residues 538-696), Nezha (residues 680-821), paracingulin (residues 620-769) and Afadin (residues 120-374).<ref>[7]</ref> 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.<ref>[12]</ref>
In vitro interaction studies were pursued to map the interaction(s) of PLEKHA 7 with p-120 Catenin (residues 538-696), [[Nezha]] (residues 680-821), [[paracingulin]] (residues 620-769) and [[Afadin]] (residues 120-374).<ref name="pmid23990464">{{cite journal | title=Binding between the junctional proteins afadin and PLEKHA7 and implication in the formation of adherens junction in epithelial cells | author=Kurita S, Yamada T, Rikitsu E, Ikeda W, Takai Y | journal=J Biol Chem | year=2013 | month=Oct | volume=288 | issue=41 | pages=29356-68 | doi=10.1074/jbc.M113.453464 | PMID=23990464}}</ref> 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.<ref name="pmid20808826"/>


== Function ==
== Function ==


One function of PLEKHA7 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.<ref>[10]</ref> 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.<ref>[7]</ref> PLEKHA7 knockdown studies in Madin-Darby canine kidney (MDCK) cells indicated its requirement for the AJ localization of paracingulin.<ref>[13]</ref> Furthermore, the PLEKHA7 homolog in zebrafish, Hadp1, is required for the proper heart function and morphogenesis in embryo, regulating the intracellular Ca2+ dynamics through the phosphatidylinositol 4-kinase (PIK4) pathway <ref>[18]</ref>
One function of PLEKHA7 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.<ref name="pmid19041755"/> 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.<ref name="pmid23990464"/> PLEKHA7 knockdown studies in Madin-Darby canine kidney (MDCK) cells indicated its requirement for the AJ localization of paracingulin.<ref name="pmid21454477">{{cite journal | title=A role for ZO-1 and PLEKHA7 in recruiting paracingulin to tight and adherens junctions of epithelial cells. | author=Pulimeno P, Paschoud S, Citi S. | journal=J. Biol Chem. | year=2011 | month=May | volume=286 | issue=19 | pages=16743-50. | doi=10.1074/jbc.M111.230862 | PMID=21454477}}</ref> Furthermore, the PLEKHA7 homolog in [[zebrafish]], Hadp1, is required for the proper heart function and morphogenesis in embryo, regulating the intracellular Ca2+ dynamics through the [[phosphatidylinositol 4-kinase]] (PIK4) pathway.<ref name="pmid21628396">{{cite journal | title=Hadp1, a newly identified pleckstrin homology domain protein, is required for cardiac contractility in zebrafish. | author=Wythe JD, Jurynec MJ, Urness LD, Jones CA, Sabeh MK, Werdich AA, Sato M, Yost HJ, Grunwald DJ, Macrae CA, Li DY. | journal=Dis Model Mech. | year=2011 | month=Sep | volume=4 | issue=5 | pages=607-21. | doi=10.1242/dmm.002204 | PMID=21628396}}</ref>


== Clinical significance ==
== Clinical significance ==


[[Genome-wide association studies]] suggest that PLEKHA7 is associated with blood pressure and hypertension<ref name=" pmid20414254">{{cite journal | title=Recapitulation of two genomewide association studies on blood pressure and essential hypertension in the Korean population. | author=Hong KW, Jin HS, Lim JE, Kim S, Go MJ, Oh B. | journal=J Hum Genet. | year=2010 | month=Jun | volume=55 | issue=6 | pages=336-41. | doi=10.1038/jhg.2010.31 | PMID=20414254}}</ref><ref name="pmid22071413">{{cite journal | title=Genetic variations in the CYP17A1 and NT5C2 genes are associated with a reduction in visceral and subcutaneous fat areas in Japanese women. | author=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. | journal=J Hum Genet. | year=2012 | month=Jan | volume=57 | issue=1 | pages=46-51 | doi=10.1038/jhg.2011.127 | PMID=22071413}}</ref><ref name="pmid19430429">{{cite journal | title=Genome-wide association study of blood pressure and hypertension. | author=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. | journal=Nat Genet. | year=2009 | month=Jun | volume=41 | issue=6 | pages=677-87 | doi=10.1038/ng.384 | PMID=19430429}}</ref><ref name="pmid21963141">{{cite journal | title=Genetic variations in CYP17A1, CACNB2 and PLEKHA7 are associated with blood pressure and/or hypertension in She ethnic minority of China. | author=Lin Y, Lai X, Chen B, Xu Y, Huang B, Chen Z, Zhu S, Yao J, Jiang Q, Huang H, Wen J, Chen G. | journal=Atherosclerosis. | year=2011 | month=Dec | volume=219 | issue=2 | pages=709-14. | doi=10.1016/j.atherosclerosis.2011.09.006 | PMID=21963141}}</ref> and primary angle closure [[glaucoma]].<ref name="pmid23840785">{{cite journal | title=Association of genetic variants with primary angle closure glaucoma in two different populations. | author=Awadalla MS, Thapa SS, Hewitt AW, Burdon KP, Craig JE. | journal=PLoS One | year=2013 | month=Jun | volume=8 | issue=6 | pages=e67903 | doi=10.1371/journal.pone.0067903 | PMID=23840785}}</ref><ref name="pmid23505305">{{cite journal | title=Genotype-phenotype analysis of SNPs associated with primary angle closure glaucoma (rs1015213, rs3753841 and rs11024102) and ocular biometry in the EPIC-Norfolk Eye Study. | author=Day AC, Luben R, Khawaja AP, Low S, Hayat S, Dalzell N, Wareham NJ, Khaw KT, Foster PJ. | journal=Br J Ophthalmol. | year=2013 | month=Jun | volume=97 | issue=6 | pages=704-7 | doi=10.1136/bjophthalmol-2012-302969 | PMID=23505305}}</ref><ref name="pmid23847314">{{cite journal | title=Association study in a South Indian population supports rs1015213 as a risk factor for primary angle closure. | author=Duvesh R, Verma A, Venkatesh R, Kavitha S, Ramulu PY, Wojciechowski R, Sundaresan P. | journal=Invest Ophthalmol Vis Sci. | year=2013 | month=Aug | volume=54 | issue=8 | pages=5624-8 | doi=10.1167/iovs.13-12186 | PMID=23847314}}</ref><ref name="pmid23920366">{{cite journal | title=Lack of association between primary angle-closure glaucoma susceptibility loci and the ocular biometric parameters anterior chamber depth and axial length. | author=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 | journal=Invest Ophthalmol Vis Sci | year=2013 | month=Aug | volume=54 | issue=8 | pages=5824-8 | doi=10.1167/iovs.13-11901 | PMID=23920366}}</ref><ref name="pmid24474268">{{cite journal | title=Genotype-Phenotype Correlation Analysis for Three Primary Angle Closure Glaucoma Associated Genetic Polymorphisms. | author=Wei X, Nongpiur ME, De Leon JM, Baskaran M, Perera SA, How AC, Vithana EN, Khor CC, Aung T. | journal=Invest Ophthalmol Vis Sci | year=2014 | month=Jan | volume=55 | issue=2 | pages=1143-8 | doi=10.1167/iovs.13-13552 | PMID=24474268}}</ref><ref name="pmid22922875">{{cite journal | title=Genome-wide association analyses identify three new susceptibility loci for primary angle closure glaucoma. | author=Vithana EN, Khor CC, Qiao C, Nongpiur ME, George R, Chen LJ, Do T, Abu-Amero K, Huang CK, Low S, Tajudin LS, 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 do N, 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. | journal=Nat Genet. | year=2012 | month=Oct | volume=44 | issue=10 | pages=1142-6 | doi=10.1038/ng.2390 | PMID=22922875}}</ref><ref name="pmid24282630">{{cite journal | title=An extensive replication study on three new susceptibility Loci of primary angle closure glaucoma in han Chinese: jiangsu eye study. | author=Shi H, Zhu R, Hu N, Shi J, Zhang J, Jiang L, Jiang H, Guan H. | journal=J Ophthalmol. | year=2013 | month=Jan | volume=641596 | doi=10.1155/2013/641596 | PMID=24282630}}</ref> Also, an increased expression of PLEKHA7 in invasive lobular breast cancer has been reported.<ref name="pmid22542108">{{cite journal | title=Genetic up-regulation and overexpression of PLEKHA7 differentiates invasive lobular carcinomas from invasive ductal carcinomas. | author=Castellana B, Escuin D, Pérez-Olabarria M, Vázquez T, Muñoz J, Peiró G, Barnadas A, Lerma E. | journal=Hum Pathol. | year=2012 | month=Nov | volume=43 | issue=11 | pages=1902-9 | doi=10.1016/j.humpath.2012.01.017 | PMID=22542108}}</ref>
Genome-wide association studies suggest that PLEKHA7 is associated with blood pressure and hypertension<ref>[5][6][8][9]</ref> and primary angle closure glaucoma.<ref>[1] [3][4][11][14][16][17]</ref> Also, an increased expression of PLEKHA7 in invasive lobular breast cancer has been reported.<ref>[2]</ref>


== References ==
== References ==


{{reflist}}
{{reflist|2}}

== Further reading ==

*<1. 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 (Jun 2013) 28; 8(6) :e67903. doi: 10.1371/journal.pone.0067903. Print 2013 PMID 23840785/>

*<2. 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.(Nov 2012) Hum Pathol. 43 (11): 1902-9. doi: 10.1016/j.humpath.2012.01.017. PMID 22542108/>

*<3. 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. (Jun 2013) Br J Ophthalmol. ;97 (6):704-7. doi: 10.1136/bjophthalmol-2012-302969. Epub 2013 Mar 15. PMID 23505305/>

*<4. 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. (Aug 2013) Invest Ophthalmol Vis Sci. 54 (8):5624-8. doi: 10.1167/iovs.13-12186. 2013 Aug 19; PMID 23847314/>

*<5. 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. J Hum Genet. (Jun 2010); 55(6):336-41. doi: 10.1038/jhg.2010.31. PMID 20414254 />

*<6. 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. J Hum Genet. (Jan 2012) 57(1):46-51. doi: 10.1038/jhg.2011.127. />

*<7. 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/>

*<8. 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. Nat Genet. (Jun 2009); 41(6): 677-87. doi: 10.1038/ng.384. PMID 21963141/>
*<9. 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. (Dec 2011) 219 (2): 709-14. doi: 10.1016/j.atherosclerosis.2011.09.006 PMID 21963141/>

⚫
*<10. Meng W, Mushika Y, Ichii T, Takeichi M. Anchorage of microtubule minus ends to adherens junctions regulates epithelial cell-cell contacts. Cell. (Nov 2008) 28 135(5): 948-59. doi: 10.1016/j.cell.2008.09.040. PMID 19041755/>

*<11. 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. (Aug. 2013) Invest Ophthalmol Vis Sci 54 (8):5824-8. doi: 10.1167/iovs.13-11901. PMID 23920366/>

*<12. 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.(Aug 2010) PLoS One.5 (8): e12207. doi: 10.1371/journal.pone.0012207. PMID 20808826/>

*<13. Pulimeno P, Paschoud S, Citi S. A role for ZO-1 and PLEKHA7 in recruiting paracingulin to tight and adherens junctions of epithelial cells. (May 2011) J. Biol Chem. 286 (19): 16743-50. doi: 10.1074/jbc.M111.230862 PMID 21454477/>

*<14. 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. (Jan 2013) J Ophthalmol. :641596. doi: 10.1155/2013/641596. PMID 24282630 />

*<15. Takai Y, Irie K, Shimizu K, Sakisaka T, Ikeda W. Nectins and nectin-like molecules: roles in cell adhesion, migration, and polarization. (Aug 2003). Cancer Sci. 94(8): 655-67. PMID 12901789

*<16. Vithana EN, Khor CC, Qiao C, Nongpiur ME, George R, Chen LJ, Do T, Abu-Amero K, Huang CK, Low S, Tajudin LS, 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 do N, 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. (Oct 2012). Nat Genet. 44(10): 1142-6. doi: 10.1038/ng.2390. PMID 22922875/>

*<17. Wei X, Nongpiur ME, De Leon JM, 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. (Jan 2014) Invest Ophthalmol Vis Sci 28 pii: iovs.13-13552v1. doi: 10.1167/iovs.13-13552 PMID 24474268 />

*<18. 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. (Sep 2011). Dis Model Mech. 4(5): 607-21. doi: 10.1242/dmm.002204. PMID 21628396/>

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{{uncategorized|date=April 2014}}
{{uncategorized|date=April 2014}}

Revision as of 12:59, 12 May 2014

Template:GNF Protein box/sandbox

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 p-120 Catenin. PLEKHA7 was identified by mass spectrometry in lysates of human intestinal carcinoma (Caco2) cells in a GST-pull down using N-terminal GST-fusion p-120 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 PLEKHA 7 with p-120 Catenin (residues 538-696), Nezha (residues 680-821), paracingulin (residues 620-769) and Afadin (residues 120-374).[3] 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.[2]

Function

One function of PLEKHA7 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.[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.[4] Furthermore, the PLEKHA7 homolog in zebrafish, Hadp1, is required for the proper heart function and morphogenesis in embryo, regulating the intracellular Ca2+ dynamics through the phosphatidylinositol 4-kinase (PIK4) pathway.[5]

Clinical significance

Genome-wide association studies suggest that PLEKHA7 is associated with blood pressure and hypertension[6][7][8][9] and primary angle closure glaucoma.[10][11][12][13][14][15][16] Also, an increased expression of PLEKHA7 in invasive lobular breast cancer has been reported.[17]

References

  1. ^ a b Meng W, Mushika Y, Ichii T, Takeichi M. (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  2. ^ a b c d Pulimeno P, Bauer C, Stutz J, Citi S. (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. PMID 20808826. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  3. ^ a b Kurita S, Yamada T, Rikitsu E, Ikeda W, Takai Y (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  4. ^ Pulimeno P, Paschoud S, Citi S. (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. PMID 21454477. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  5. ^ Wythe JD, Jurynec MJ, Urness LD, Jones CA, Sabeh MK, Werdich AA, Sato M, Yost HJ, Grunwald DJ, Macrae CA, Li DY. (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. PMID 21628396. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  6. ^ Hong KW, Jin HS, Lim JE, Kim S, Go MJ, Oh B. (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  7. ^ 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. (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ 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. (2009). "Genome-wide association study of blood pressure and hypertension". Nat Genet. 41 (6): 677–87. doi:10.1038/ng.384. PMID 19430429. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  9. ^ Lin Y, Lai X, Chen B, Xu Y, Huang B, Chen Z, Zhu S, Yao J, Jiang Q, Huang H, Wen J, Chen G. (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  10. ^ Awadalla MS, Thapa SS, Hewitt AW, Burdon KP, Craig JE. (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. PMID 23840785. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  11. ^ Day AC, Luben R, Khawaja AP, Low S, Hayat S, Dalzell N, Wareham NJ, Khaw KT, Foster PJ. (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  12. ^ Duvesh R, Verma A, Venkatesh R, Kavitha S, Ramulu PY, Wojciechowski R, Sundaresan P. (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. PMID 23847314. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  13. ^ 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 (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  14. ^ Wei X, Nongpiur ME, De Leon JM, Baskaran M, Perera SA, How AC, Vithana EN, Khor CC, Aung T. (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  15. ^ Vithana EN, Khor CC, Qiao C, Nongpiur ME, George R, Chen LJ, Do T, Abu-Amero K, Huang CK, Low S, Tajudin LS, 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 do N, 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. (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  16. ^ Shi H, Zhu R, Hu N, Shi J, Zhang J, Jiang L, Jiang H, Guan H. (2013). "An extensive replication study on three new susceptibility Loci of primary angle closure glaucoma in han Chinese: jiangsu eye study". J Ophthalmol. 641596. doi:10.1155/2013/641596. PMID 24282630. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  17. ^ Castellana B, Escuin D, Pérez-Olabarria M, Vázquez T, Muñoz J, Peiró G, Barnadas A, Lerma E. (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
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