title: Protein kinase A activates the Hippo pathway to modulate cell proliferation and differentiation.
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.
authors.affiliation: Department of Pharmacology, University of California at San Diego, La Jolla, California 92093, USA.
authors.forename: Fa-Xing
authors.initials: FX
authors.lastname: Yu
authors.forename: Yifan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hyun Woo
authors.initials: HW
authors.lastname: Park
authors.forename: Jenna L
authors.initials: JL
authors.lastname: Jewell
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.forename: Yaoting
authors.initials: Y
authors.lastname: Deng
authors.forename: Duojia
authors.initials: D
authors.lastname: Pan
authors.forename: Susan S
authors.initials: SS
authors.lastname: Taylor
authors.forename: Zhi-Chun
authors.initials: ZC
authors.lastname: Lai
authors.forename: Kun-Liang
authors.initials: KL
authors.lastname: Guan
mesh_terms: D000217:Acyltransferases; D050156:Adipogenesis; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000201:enzymology / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015290:Second Messenger Systems / Q000502:physiology; D000090742:Serine-Threonine Kinase 3; D015398:Signal Transduction; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000091102:YAP-Signaling Proteins; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D000099317:Hippo Kinases
chemical_list: D000217:Acyltransferases; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D000090742:Serine-Threonine Kinase 3; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; D020741:rho GTP-Binding Proteins; C503814:Yki protein, Drosophila; C486363:tafazzin protein, mouse; C490501:Lats1 protein, mouse; C490660:Stk4 protein, mouse; D000099317:Hippo Kinases; C522633:LATS2 protein, mouse; C490818:Stk3 protein, mouse; C499474:hpo protein, Drosophila
keywords: Hippo; PKA; YAP; adipogenesis; proliferation