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InterAKTions with FKBPs--mutational and pharmacological exploration.

Fabian AK, März A, Neimanis S, Biondi RM, Kozany C, Hausch F - PLoS ONE (2013)

Bottom Line: The FK506-binding protein 51 (FKBP51) is an Hsp90-associated co-chaperone which regulates steroid receptors and kinases.The FKBP51-Akt interaction is sensitive to the conformation of Akt1, but does not depend on the FK506-binding pocket of FKBP51.Therefore, FKBP inhibitors are unlikely to inhibit the Akt-FKBP-PHLPP network.

View Article: PubMed Central - PubMed

Affiliation: Research Group Chemical Genomics, Max Planck Institute of Psychiatry, Munich, Germany.

ABSTRACT
The FK506-binding protein 51 (FKBP51) is an Hsp90-associated co-chaperone which regulates steroid receptors and kinases. In pancreatic cancer cell lines, FKBP51 was shown to recruit the phosphatase PHLPP to facilitate dephosphorylation of the kinase Akt, which was associated with reduced chemoresistance. Here we show that in addition to FKBP51 several other members of the FKBP family bind directly to Akt. FKBP51 can also form complexes with other AGC kinases and mapping studies revealed that FKBP51 interacts with Akt via multiple domains independent of their activation or phosphorylation status. The FKBP51-Akt1 interaction was not affected by FK506 analogs or Akt active site inhibitors, but was abolished by the allosteric Akt inhibitor VIII. None of the FKBP51 inhibitors affected AktS473 phosphorylation or downstream targets of Akt. In summary, we show that FKBP51 binds to Akt directly as well as via Hsp90. The FKBP51-Akt interaction is sensitive to the conformation of Akt1, but does not depend on the FK506-binding pocket of FKBP51. Therefore, FKBP inhibitors are unlikely to inhibit the Akt-FKBP-PHLPP network.

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Related in: MedlinePlus

Schematic model of possible Hsp90-Akt-FKBP51 complexes.A FKBP51 can bind directly to Akt via its FK1 domain, but not with its FK506-binding pocket. Several other FK1-possessing FKBP homologs may bind to Akt in a similar mode. B Akt and several other kinases can bind to FKBP51 indirectly via Hsp90. C FKBP51 could assist the chaperoning of Akt by binding to Hsp90 via its TPR domain and by interacting with Akt via its FK1 domain.
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pone-0057508-g007: Schematic model of possible Hsp90-Akt-FKBP51 complexes.A FKBP51 can bind directly to Akt via its FK1 domain, but not with its FK506-binding pocket. Several other FK1-possessing FKBP homologs may bind to Akt in a similar mode. B Akt and several other kinases can bind to FKBP51 indirectly via Hsp90. C FKBP51 could assist the chaperoning of Akt by binding to Hsp90 via its TPR domain and by interacting with Akt via its FK1 domain.

Mentions: Our study supports a robust FKBP51-Akt1 interaction but we were unable to observe enhanced dephosphorylation upon FKBP51 expression. This could be due to PHLPP not being the rate-limiting phosphatase for Akt in our cells and under our cell culture conditions. According to our results the interaction of Akt and FKBP51 might be more complex than previously thought (Figure 7).


InterAKTions with FKBPs--mutational and pharmacological exploration.

Fabian AK, März A, Neimanis S, Biondi RM, Kozany C, Hausch F - PLoS ONE (2013)

Schematic model of possible Hsp90-Akt-FKBP51 complexes.A FKBP51 can bind directly to Akt via its FK1 domain, but not with its FK506-binding pocket. Several other FK1-possessing FKBP homologs may bind to Akt in a similar mode. B Akt and several other kinases can bind to FKBP51 indirectly via Hsp90. C FKBP51 could assist the chaperoning of Akt by binding to Hsp90 via its TPR domain and by interacting with Akt via its FK1 domain.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585324&req=5

pone-0057508-g007: Schematic model of possible Hsp90-Akt-FKBP51 complexes.A FKBP51 can bind directly to Akt via its FK1 domain, but not with its FK506-binding pocket. Several other FK1-possessing FKBP homologs may bind to Akt in a similar mode. B Akt and several other kinases can bind to FKBP51 indirectly via Hsp90. C FKBP51 could assist the chaperoning of Akt by binding to Hsp90 via its TPR domain and by interacting with Akt via its FK1 domain.
Mentions: Our study supports a robust FKBP51-Akt1 interaction but we were unable to observe enhanced dephosphorylation upon FKBP51 expression. This could be due to PHLPP not being the rate-limiting phosphatase for Akt in our cells and under our cell culture conditions. According to our results the interaction of Akt and FKBP51 might be more complex than previously thought (Figure 7).

Bottom Line: The FK506-binding protein 51 (FKBP51) is an Hsp90-associated co-chaperone which regulates steroid receptors and kinases.The FKBP51-Akt interaction is sensitive to the conformation of Akt1, but does not depend on the FK506-binding pocket of FKBP51.Therefore, FKBP inhibitors are unlikely to inhibit the Akt-FKBP-PHLPP network.

View Article: PubMed Central - PubMed

Affiliation: Research Group Chemical Genomics, Max Planck Institute of Psychiatry, Munich, Germany.

ABSTRACT
The FK506-binding protein 51 (FKBP51) is an Hsp90-associated co-chaperone which regulates steroid receptors and kinases. In pancreatic cancer cell lines, FKBP51 was shown to recruit the phosphatase PHLPP to facilitate dephosphorylation of the kinase Akt, which was associated with reduced chemoresistance. Here we show that in addition to FKBP51 several other members of the FKBP family bind directly to Akt. FKBP51 can also form complexes with other AGC kinases and mapping studies revealed that FKBP51 interacts with Akt via multiple domains independent of their activation or phosphorylation status. The FKBP51-Akt1 interaction was not affected by FK506 analogs or Akt active site inhibitors, but was abolished by the allosteric Akt inhibitor VIII. None of the FKBP51 inhibitors affected AktS473 phosphorylation or downstream targets of Akt. In summary, we show that FKBP51 binds to Akt directly as well as via Hsp90. The FKBP51-Akt interaction is sensitive to the conformation of Akt1, but does not depend on the FK506-binding pocket of FKBP51. Therefore, FKBP inhibitors are unlikely to inhibit the Akt-FKBP-PHLPP network.

Show MeSH
Related in: MedlinePlus