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Article: Focal adhesion kinase-Tyr 407 and -Tyr 397 exhibit antagonistic effects on blood-testis barrier dynamics in the rat

TitleFocal adhesion kinase-Tyr 407 and -Tyr 397 exhibit antagonistic effects on blood-testis barrier dynamics in the rat
Authors
Issue Date2012
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
Citation
Proceedings Of The National Academy Of Sciences Of The United States Of America, 2012, v. 109 n. 31, p. 12562-12567 How to Cite?
AbstractFocal adhesion kinase (FAK), a nonreceptor protein tyrosine kinase, displays phosphorylation-dependent localization in the seminiferous epithelium of adult rat testes. FAK is an integrated component of the blood-testis barrier (BTB) involved in regulating Sertoli cell adhesion via its effects on the occludin-zonula occludens-1 complex. Herein, we report that p-FAK-Tyr 407 and p-FAK-Tyr 397 display restricted spatiotemporal and almost mutually exclusive localization in the epithelium, affecting BTB dynamics antagonistically, with the former promoting and the latter disrupting the Sertoli cell tight junction-permeability barrier function. Using primary cultured Sertoli cells as an in vitro model that mimics the BTB in vivo both functionally and ultrastructurally, effects of FAK phosphorylation on BTB function were studied by expressing nonphosphorylatable and phosphomimetic mutants, with tyrosine replaced by phenylalanine (F) and glutamate (E), respectively. Compared with WT FAK, Y407E and Y397F mutations each promoted barrier function, and the promoting effect of the Y407E mutant was abolished in the Y397E-Y407E double mutant, demonstrating antagonism between Tyr 407 and Tyr 397. Furthermore, Y407E mutation induced the recruitment of actin-related protein 3 to the Sertoli cell-cell interface, where it became more tightly associated with neuronal Wiskott-Aldrich syndrome protein, promoting actin-related protein 2/3 complex activity. Conversely, Y407F mutation reduced the rate of actin polymerization at the Sertoli cell BTB. In summary, FAK-Tyr 407 phosphorylation promotes BTB integrity by strengthening the actin filament-based cytoskeleton. FAK serves as a bifunctional molecular "switch" to direct the cyclical disassembly and reassembly of the BTB during the epithelial cycle of spermatogenesis, depending on its phosphorylation status, to facilitate the transit of preleptotene spermatocytes across the BTB.
Persistent Identifierhttp://hdl.handle.net/10722/179293
ISSN
2015 Impact Factor: 9.423
2015 SCImago Journal Rankings: 6.883
PubMed Central ID
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorLie, PPYen_US
dc.contributor.authorMruk, DDen_US
dc.contributor.authorMok, KWen_US
dc.contributor.authorSu, Len_US
dc.contributor.authorLee, WMen_US
dc.contributor.authorCheng, CYen_US
dc.date.accessioned2012-12-19T09:53:54Z-
dc.date.available2012-12-19T09:53:54Z-
dc.date.issued2012en_US
dc.identifier.citationProceedings Of The National Academy Of Sciences Of The United States Of America, 2012, v. 109 n. 31, p. 12562-12567en_US
dc.identifier.issn0027-8424en_US
dc.identifier.urihttp://hdl.handle.net/10722/179293-
dc.description.abstractFocal adhesion kinase (FAK), a nonreceptor protein tyrosine kinase, displays phosphorylation-dependent localization in the seminiferous epithelium of adult rat testes. FAK is an integrated component of the blood-testis barrier (BTB) involved in regulating Sertoli cell adhesion via its effects on the occludin-zonula occludens-1 complex. Herein, we report that p-FAK-Tyr 407 and p-FAK-Tyr 397 display restricted spatiotemporal and almost mutually exclusive localization in the epithelium, affecting BTB dynamics antagonistically, with the former promoting and the latter disrupting the Sertoli cell tight junction-permeability barrier function. Using primary cultured Sertoli cells as an in vitro model that mimics the BTB in vivo both functionally and ultrastructurally, effects of FAK phosphorylation on BTB function were studied by expressing nonphosphorylatable and phosphomimetic mutants, with tyrosine replaced by phenylalanine (F) and glutamate (E), respectively. Compared with WT FAK, Y407E and Y397F mutations each promoted barrier function, and the promoting effect of the Y407E mutant was abolished in the Y397E-Y407E double mutant, demonstrating antagonism between Tyr 407 and Tyr 397. Furthermore, Y407E mutation induced the recruitment of actin-related protein 3 to the Sertoli cell-cell interface, where it became more tightly associated with neuronal Wiskott-Aldrich syndrome protein, promoting actin-related protein 2/3 complex activity. Conversely, Y407F mutation reduced the rate of actin polymerization at the Sertoli cell BTB. In summary, FAK-Tyr 407 phosphorylation promotes BTB integrity by strengthening the actin filament-based cytoskeleton. FAK serves as a bifunctional molecular "switch" to direct the cyclical disassembly and reassembly of the BTB during the epithelial cycle of spermatogenesis, depending on its phosphorylation status, to facilitate the transit of preleptotene spermatocytes across the BTB.en_US
dc.languageengen_US
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.orgen_US
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of Americaen_US
dc.subject.meshActins - Genetics - Metabolismen_US
dc.subject.meshAmino Acid Substitutionen_US
dc.subject.meshAnimalsen_US
dc.subject.meshBlood-Testis Barrier - Cytology - Enzymologyen_US
dc.subject.meshCytoskeleton - Genetics - Metabolismen_US
dc.subject.meshFocal Adhesion Kinase 1 - Genetics - Metabolismen_US
dc.subject.meshMaleen_US
dc.subject.meshMembrane Proteins - Genetics - Metabolismen_US
dc.subject.meshMutation, Missenseen_US
dc.subject.meshPhosphoproteins - Genetics - Metabolismen_US
dc.subject.meshPhosphorylation - Geneticsen_US
dc.subject.meshProtein Multimerization - Physiologyen_US
dc.subject.meshRatsen_US
dc.subject.meshSertoli Cells - Cytology - Metabolismen_US
dc.subject.meshSpermatocytes - Cytology - Enzymologyen_US
dc.subject.meshSpermatogenesis - Physiologyen_US
dc.subject.meshTight Junctions - Enzymology - Geneticsen_US
dc.subject.meshWiskott-Aldrich Syndrome Protein - Genetics - Metabolismen_US
dc.titleFocal adhesion kinase-Tyr 407 and -Tyr 397 exhibit antagonistic effects on blood-testis barrier dynamics in the raten_US
dc.typeArticleen_US
dc.identifier.emailLee, WM: hrszlwm@hku.hken_US
dc.identifier.authorityLee, WM=rp00728en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1073/pnas.1202316109en_US
dc.identifier.pmid22797892-
dc.identifier.pmcidPMC3412022-
dc.identifier.scopuseid_2-s2.0-84864510712en_US
dc.identifier.hkuros209790-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84864510712&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume109en_US
dc.identifier.issue31en_US
dc.identifier.spage12562en_US
dc.identifier.epage12567en_US
dc.identifier.isiWOS:000307538200061-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridLie, PPY=15839862700en_US
dc.identifier.scopusauthoridMruk, DD=6701823934en_US
dc.identifier.scopusauthoridMok, KW=38961643800en_US
dc.identifier.scopusauthoridSu, L=34871019700en_US
dc.identifier.scopusauthoridLee, WM=24799156600en_US
dc.identifier.scopusauthoridCheng, CY=7404797787en_US

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