Title

The Hsp90 kinase co-chaperone Cdc37 regulates tau stability and phosphorylation dynamics.

Journal

The Journal of biological chemistry

Volume

286

Issue

None

Pages

16976-83

Date

2011-05-13

Authors

Dickey CA | Koren J 3rd | Jinwal UK | Abisambra JF | Jin Y | Johnson AG | Jones JR | Lawson LY | Li Q | O'Leary JC 3rd | Trotter JH | Vestal GD | Weeber EJ

Previous work showed that Hsp90 inhibition with 17-AAG reduced phospho-tau levels in vivo (16, 23). We speculated that Cdc37 might modulate Hsp90 inhibitor efficacy for phosphotau. M17 cells were transfected with Cdc37 siRNA and then treated with 1 μM 17-AAG for 24 h. Indeed, reducing Cdc37 synergized with Hsp90 inhibition to reduce tau levels more potently than either condition alone (Fig. 6A).

This coordination of kinase triage decisions by Hsp90 requires the co-chaperone Cdc37 (cell division cycle protein 37). The Hsp90/Cdc37 machine is essential for the maturation of a number of kinases, including Akt

Quantification of the Western blot showed that Cdc37 knockdown reduced phospho-Thr-231, phospho-Ser-199/Ser-202, phospho-Ser-396/Ser-404, and phospho-Ser-262/Ser-356 tau.

Western blot analysis for a panel of tau kinases showed that only the levels of endogenous Cdk5 and Akt were significantly reduced by Cdc37 siRNA; the levels of GSK3-Beta and Mark2 (microtubule affinity regulating kinase 2) were largely unchanged

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