Kuravi VK, Kurischko C, Puri M, Luca FC

Saccharomyces cerevisiae Cbk1 kinase is a LATS/NDR tumor suppressor orthologue and component of the RAM signaling network. Cbk1 was previously implicated in regulating polarized morphogenesis, gene expression and cell integrity. Here, we establish that Cbk1 is critical for heat shock and cell wall stress signaling via Bck2, a protein associated ...

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with the Pkc1-Mpk1 cell integrity pathway. We demonstrate that cbk1 and bck2 loss-of-function mutations prevent Mpk1 kinase activation and Mpk1-dependent gene expression, but do not disrupt Mpk1 Thr(190)/Tyr(192) phosphorylation. Bck2 overexpression partially restores Mpk1-dependent Rlm1 transcription factor activity in cbk1 mutants, suggesting that Bck2 functions downstream of Cbk1. We demonstrate that Bck2 precisely colocalizes with the MAP kinase phosphatase Sdp1. During heat shock, Bck2 and Sdp1 transiently redistribute from nuclei and the cytosol to mitochondria and other cytoplasmic puncta before returning to their pre-stressed localization patterns. Significantly, Cbk1 inhibition delays the return of Bck2 and Sdp1 to their pre-stressed localization patterns and delays Mpk1 Thr(190)/Tyr(192) dephosphorylation upon heat shock adaptation. We conclude that Cbk1 and Bck2 are required for Mpk1 activation during heat shock and cell wall stress and for Mpk1 dephosphorylation during heat shock adaptation. These data provide the first evidence that Cbk1 kinase regulates MAP kinase-dependent stress signaling and provide mechanistic insight into Sdp1 phosphatase regulation.

Date: Oct. 26, 2011

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