CDK-Dependent Hsp70 Phosphorylation Controls G1 Cyclin Abundance and Cell-Cycle Progression

Abstract

SummaryIn budding yeast, the essential functions of Hsp70 chaperones Ssa1–4 are regulated through expression level, isoform specificity, and cochaperone activity. Suggesting a novel regulatory paradigm, we find that phosphorylation of Ssa1 T36 within a cyclin-dependent kinase (CDK) consensus site conserved among Hsp70 proteins alters cochaperone and client interactions. T36 phosphorylation triggers displacement of Ydj1, allowing Ssa1 to bind the G1 cyclin Cln3 and promote its degradation. The stress CDK Pho85 phosphorylates T36 upon nitrogen starvation or pheromone stimulation, destabilizing Cln3 to delay onset of S phase. In turn, the mitotic CDK Cdk1 phosphorylates T36 to block Cln3 accumulation in G2/M. Suggesting broad conservation from yeast to human, CDK-dependent phosphorylation of Hsc70 T38 similarly regulates Cyclin D1 binding and stability. These results establish an active role for Hsp70 chaperones as signal transducers mediating growth control of G1 cyclin abundance and activity.

Melanoma Therapeutic Strategies that Select against Resistance by Exploiting MYC-Driven Evolutionary Convergence

“…Another interesting compound identified in the screen was Tigecycline, whose selectivity could be extended to several BRAFi-resistant models (Figure S6E). In parallel, we examined candidate MYC synthetic lethal partners previously identified in other cancer types using a panel of matched parental and BRAFi-resistant cells (Chipumuro et al, 2014; Goga et al, 2007; Martins et al, 2015; Toledo et al, 2011; Truman et al, 2012; Yang et al, 2010). Of these candidates, the multi-targeted tyrosine kinase inhibitor, dasatinib, was selectively lethal in 6 out of 6 MYC-dependent, PLX4720-resistant clones relative to matched parental cells (Figures 6B and S6F).…”

Phosphate-Activated Cyclin-Dependent Kinase Stabilizes G1 Cyclin To Trigger Cell Cycle Entry

“…Interestingly, during the revision process of the manuscript, the group of Kron and collaborators described that Pho85/Pcl2 controlled the amount of Cln3 through the activation of Hsp70 in response to nitrogen, pointing to Pho85 as a general controller of Cln3 in response to variations in nutrient levels (44).…”

Multiple Pho85-Dependent Mechanisms Control G1 Cyclin Abundance in Response to Nutrient Stress

“…Coincidentally, however, a recent study by Truman et al shows the opposite effect of Pho85 on Cln3 stability (7). The authors of this study demonstrate that in response to nitrogen starvation or after prolonged exposure of yeast cells to mating pheromone, Pho85 activity promotes destabilization of Cln3.…”

“…Although Ssa1 T36 is not phosphorylated by Cln3-Cdk1, this site was found to be phosphorylated by mitotic Clb-Cdk1 complexes. Truman et al propose that this mechanism keeps Cln3 levels low in mitosis (7). In fact, such differential specificity fits well to a model of changing Cdk1 specificity that states that mitotic cyclin-Cdk1 complexes have a higher intrinsic specificity than G 1 -and S-phase complexes toward the phosphoacceptor peptide (9).…”

“…This hypothesis awaits experimental validation. Similarly, the role of the Cln3-Ssa1 interaction reported by Truman et al (7) needs to be further investigated. They propose that phosphorylation of Cln3 and the Cln3-Ssa1 interaction are each necessary but neither is individually sufficient for the degradation of Cln3.…”