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.
Highlights
Akt is a member of the serine-threonine kinase AGC superfamily and has three isoforms (Akt1, Akt2, Akt3)
No interaction was observed with purified Cyp40 [28], a closely related immunophilin, which has a tetratricopeptide repeat domain (TPR) domain and binds to Hsp90 but which lacks an FK506-binding domain
Since PHLPP is regulating Akt phosphorylation and is proposed to be part of the Akt-FK506-binding protein 51 (FKBP51)-PHLPP complex [23] we explored whether FK506-binding proteins (FKBPs) inhibitors affected the FKBP51-PHLPP complex
Summary
Akt ( called PKB) is a member of the serine-threonine kinase AGC superfamily and has three isoforms (Akt, Akt, Akt). Akt ( called PKB) is a member of the serine-threonine kinase AGC superfamily and has three isoforms (Akt, Akt, Akt3) It constitutes an important node in diverse signaling cascades and plays an essential role in cell survival, growth, migration, proliferation, polarity, metabolism, and cell cycle progression [1]. The Akt inhibitor perifosine is currently evaluated in phase III clinical trials against various cancers whereas the allosteric Akt inhibitor MK2206 has reached phase I. To overcome the problem of feedback regulation within the PI3K/Akt pathway dual PI3K/mTOR inhibitors seem to be promising and several companies pursue such compounds in phase I or phase II clinical trialsCourtney et al [5]
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