RGD Reference Report - Focal adhesion kinase-Tyr407 and -Tyr397 exhibit antagonistic effects on blood-testis barrier dynamics in the rat. - Rat Genome Database

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Focal adhesion kinase-Tyr407 and -Tyr397 exhibit antagonistic effects on blood-testis barrier dynamics in the rat.

Authors: Lie, PP  Mruk, DD  Mok, KW  Su, L  Lee, WM  Cheng, CY 
Citation: Lie PP, etal., Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12562-7. doi: 10.1073/pnas.1202316109. Epub 2012 Jul 12.
RGD ID: 11530040
Pubmed: PMID:22797892   (View Abstract at PubMed)
PMCID: PMC3412022   (View Article at PubMed Central)
DOI: DOI:10.1073/pnas.1202316109   (Journal Full-text)

Focal 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.



Gene Ontology Annotations    Click to see Annotation Detail View

Cellular Component

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Actr3Ratapical tubulobulbar complex  IDA  RGD 

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
WaslRatcytoskeletal protein binding  IPIActr3 (Rattus norvegicus) RGD 
Actr3Ratprotein binding  IPIWasl (Rattus norvegicus) RGD 

Objects Annotated

Genes (Rattus norvegicus)
Actr3  (actin related protein 3)
Wasl  (WASP like actin nucleation promoting factor)


Additional Information