InterAKTions with FKBPs - mutational and pharmacological exploration

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

Protein kinase B controls transcriptional programs that direct cytotoxic T cell fate but is dispensable for T cell metabolism

SummaryIn cytotoxic T cells (CTL), Akt, also known as protein kinase B, is activated by the T cell antigen receptor (TCR) and the cytokine interleukin 2 (IL-2). Akt can control cell metabolism in many cell types but whether this role is important for CTL function has not been determined. Here we have shown that Akt does not mediate IL-2- or TCR-induced cell metabolic responses; rather, this role is assumed by other Akt-related kinases. There is, however, a nonredundant role for sustained and strong activation of Akt in CTL to coordinate the TCR- and IL-2-induced transcriptional programs that control expression of key cytolytic effector molecules, adhesion molecules, and cytokine and chemokine receptors that distinguish effector versus memory and naive T cells. Akt is thus dispensable for metabolism, but the strength and duration of Akt activity dictates the CTL transcriptional program and determines CTL fate

Chern Classes and Compatible Power Operations in Inertial K-theory

Let [X/G] be a smooth Deligne-Mumford quotient stack. In a previous paper the authors constructed a class of exotic products called inertial products on K(I[X/G]), the Grothendieck group of vector bundles on the inertia stack I[X/G]. In this paper we develop a theory of Chern classes and compatible power operations for inertial products. When G is diagonalizable these give rise to an augmented $\lambda$-ring structure on inertial K-theory. One well-known inertial product is the virtual product. Our results show that for toric Deligne-Mumford stacks there is a $\lambda$-ring structure on inertial K-theory. As an example, we compute the $\lambda$-ring structure on the virtual K-theory of the weighted projective lines P(1,2) and P(1,3). We prove that after tensoring with C, the augmentation completion of this $\lambda$-ring is isomorphic as a $\lambda$-ring to the classical K-theory of the crepant resolutions of singularities of the coarse moduli spaces of the cotangent bundles $T^*P(1,2)$ and $T^*P(1,3)$, respectively. We interpret this as a manifestation of mirror symmetry in the spirit of the Hyper-Kaehler Resolution Conjecture.Comment: Many improvements. Special thanks to the referee for helpful suggestions. To appear in Annals of K-Theory. arXiv admin note: text overlap with arXiv:1202.060

The surgery exact sequence, K-theory and the signature operator

The main result of this paper is a new and direct proof of the natural transformation from the surgery exact sequence in topology to the analytic K-theory sequence of Higson and Roe. Our approach makes crucial use of analytic properties and new index theorems for the signature operator on Galois coverings with boundary. These are of independent interest and form the second main theme of the paper. The main technical novelty is the use of large scale index theory for Dirac type operators that are perturbed by lower order operators.Comment: 29 pages, AMS-LaTeX; v2: small corrections and (hopefully) improved exposition, as suggested by the referee. Final version, to appear in Annals of K-Theor