Regulation of G(0) entry by the Pho80–Pho85 cyclin–CDK complex

Abstract

Eukaryotic cell proliferation is controlled by growth factors and essential nutrients. In their absence, cells may enter into a quiescent state (G(0)). In Saccharomyces cerevisiae, the conserved protein kinase A (PKA) and rapamycin-sensitive TOR (TORC1) pathways antagonize G(0) entry in response to carbon and/or nitrogen availability primarily by inhibiting the PAS kinase Rim15 function. Here, we show that the phosphate-sensing Pho80–Pho85 cyclin–cyclin-dependent kinase (CDK) complex also participates in Rim15 inhibition through direct phosphorylation, thereby effectively sequestering Rim15 in the cytoplasm via its association with 14-3-3 proteins. Inactivation of either Pho80–Pho85 or TORC1 causes dephosphorylation of the 14-3-3-binding site in Rim15, thus enabling nuclear import of Rim15 and induction of the Rim15-controlled G(0) program. Importantly, we also show that Pho80–Pho85 and TORC1 converge on a single amino acid in Rim15. Thus, Rim15 plays a key role in G(0) entry through its ability to integrate signaling from the PKA, TORC1, and Pho80–Pho85 pathways