5′-AMP Activates the AMP-activated Protein Kinase Cascade, and Ca2+/Calmodulin Activates the Calmodulin-dependent Protein Kinase I Cascade, via Three Independent Mechanisms

ABSTRACT Yvh1p, a dual-specific protein phosphatase induced specifically by nitrogen starvation, regulates cell growth as well as initiation and completion of sporulation. We demonstrate that yvh1disruption mutants are also unable to accumulate glycogen in stationary phase. A catalytically inactive variant of yvh1 (C117S) and a DNA fragment encoding only the Yvh1p C-terminal 159 amino acids (which completely lacks the phosphatase domain) complement all three phenotypes as well as the wild-type allele; no complementation occurs with a fragment encoding only the C-terminal 74 amino acids. These observations argue that phosphatase activity is not required for the Yvh1p functions we measured. Mutations which decrease endogenous cyclic AMP (cAMP) levels partially suppress the sporulation and glycogen accumulation defects. In addition, reporter gene expression supported by a DRR2 promoter fragment, containing two stress response elements known to respond to cAMP-protein kinase A, decreases in ayvh1 disruption mutant. Therefore, our results identify three cellular processes that both require Yvh1p and respond to alterations in cAMP, and they lead us to suggest that Yvh1p may be a participant in and/or a contributor to regulation of the cAMP-dependent protein kinase cascade. The fact that decreasing the levels of cAMP alleviates the need for Yvh1p function supports this suggestion.

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The Croonian Lecture 1998. Identification of a protein kinase cascade of major importance in insulin signal transduction

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.1999.0399 ◽

1999 ◽

Vol 354 (1382) ◽

pp. 485-495 ◽

Cited By ~ 116

Author(s):

Philip Cohen

Keyword(s):

Protein Kinase ◽

Glycogen Synthase ◽

European Population ◽

Glycogen Synthase Kinase 3 ◽

Dependent Protein Kinase ◽

Insulin Signal Transduction ◽

Intracellular Proteins ◽

Kinase Cascade ◽

Dependent Protein ◽

Protein Kinase Cascade

Diabetes affects 3% of the European population and 140 million people worldwide, and is largely a disease of insulin resistance in which the tissues fail to respond to this hormone. This emphasizes the importance of understanding how insulin signals to the cell's interior. We have recently dissected a protein kinase cascade that is triggered by the formation of the insulin ‘second messenger’ phosphatidylinositide (3,4,5) trisphosphate (PtdIns(3,4,5)P 3 ) and which appears to mediate many of the metabolic actions of this hormone. The first enzyme in the cascade is termed 3–phosphoinositide–dependent protein kinase–1 (PDK1), because it only activates protein kinase B (PKB), the next enzyme in the pathway, in the presence of PtdIns(3,4,5)P 3 . PKB then inactivates glycogen synthase kinase–3 (GSK3). PDK1, PKB and GSK3 regulate many physiological events by phosphorylating a variety of intracellular proteins. In addition, PKB plays an important role in mediating protection against apoptosis by survival factors, such as insulin–like growth factor–1.

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