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InterAKTions with FKBPs--mutational and pharmacological exploration.
PLoS One. 2013; 8(2):e57508.Plos

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.

Authors+Show Affiliations

Research Group Chemical Genomics, Max Planck Institute of Psychiatry, Munich, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23469007

Citation

Fabian, Anne-Katrin, et al. "InterAKTions With FKBPs--mutational and Pharmacological Exploration." PloS One, vol. 8, no. 2, 2013, pp. e57508.
Fabian AK, März A, Neimanis S, et al. InterAKTions with FKBPs--mutational and pharmacological exploration. PLoS One. 2013;8(2):e57508.
Fabian, A. K., März, A., Neimanis, S., Biondi, R. M., Kozany, C., & Hausch, F. (2013). InterAKTions with FKBPs--mutational and pharmacological exploration. PloS One, 8(2), e57508. https://doi.org/10.1371/journal.pone.0057508
Fabian AK, et al. InterAKTions With FKBPs--mutational and Pharmacological Exploration. PLoS One. 2013;8(2):e57508. PubMed PMID: 23469007.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - InterAKTions with FKBPs--mutational and pharmacological exploration. AU - Fabian,Anne-Katrin, AU - März,Andreas, AU - Neimanis,Sonja, AU - Biondi,Ricardo M, AU - Kozany,Christian, AU - Hausch,Felix, Y1 - 2013/02/28/ PY - 2012/11/19/received PY - 2013/01/22/accepted PY - 2013/3/8/entrez PY - 2013/3/8/pubmed PY - 2013/9/11/medline SP - e57508 EP - e57508 JF - PloS one JO - PLoS One VL - 8 IS - 2 N2 - 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. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/23469007/InterAKTions_with_FKBPs__mutational_and_pharmacological_exploration_ L2 - https://dx.plos.org/10.1371/journal.pone.0057508 DB - PRIME DP - Unbound Medicine ER -