Abstract
The Hippo tumor suppressor pathway plays an important role in tissue homeostasis that ensures development of functional organs at proper size. The YAP transcription coactivator is a major effector of the Hippo pathway and is phosphorylated and inactivated by the Hippo pathway kinases Lats1/2. It has recently been shown that YAP activity is regulated by G-protein-coupled receptor signaling. Here we demonstrate that cyclic adenosine monophosphate (cAMP), a second messenger downstream from Gαs-coupled receptors, acts through protein kinase A (PKA) and Rho GTPases to stimulate Lats kinases and YAP phosphorylation. We also show that inactivation of YAP is crucial for PKA-induced adipogenesis. In addition, PKA activation in Drosophila inhibits the expression of Yorki (Yki, a YAP ortholog) target genes involved in cell proliferation and death. Taken together, our study demonstrates that Hippo-YAP is a key signaling branch of cAMP and PKA and reveals new insight into mechanisms of PKA in regulating a broad range of cellular functions.
Keywords:
Hippo; PKA; YAP; adipogenesis; proliferation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acyltransferases
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Adipogenesis
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Animals
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Cell Differentiation*
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Cell Line
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Cell Proliferation
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Cyclic AMP / metabolism
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Cyclic AMP-Dependent Protein Kinases / metabolism*
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Drosophila Proteins / antagonists & inhibitors
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Drosophila Proteins / metabolism*
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Drosophila melanogaster / enzymology
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Drosophila melanogaster / metabolism
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Enzyme Activation
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Humans
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Intracellular Signaling Peptides and Proteins / metabolism*
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Mice
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / metabolism
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Phosphorylation
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Protein Serine-Threonine Kinases / metabolism*
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Second Messenger Systems / physiology
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Serine-Threonine Kinase 3
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Signal Transduction*
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Trans-Activators / antagonists & inhibitors
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Trans-Activators / metabolism
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / metabolism
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Tumor Suppressor Proteins / metabolism
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YAP-Signaling Proteins
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rho GTP-Binding Proteins / metabolism
Substances
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Drosophila Proteins
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Intracellular Signaling Peptides and Proteins
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Nuclear Proteins
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Trans-Activators
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Transcription Factors
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Tumor Suppressor Proteins
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YAP-Signaling Proteins
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Yki protein, Drosophila
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Cyclic AMP
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Acyltransferases
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tafazzin protein, mouse
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Lats1 protein, mouse
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Stk4 protein, mouse
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LATS2 protein, mouse
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Protein Serine-Threonine Kinases
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Serine-Threonine Kinase 3
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Stk3 protein, mouse
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hpo protein, Drosophila
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Cyclic AMP-Dependent Protein Kinases
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rho GTP-Binding Proteins