Protein kinase A activates the Hippo pathway to modulate cell proliferation and differentiation

doi:10.1101/GAD.219402.113

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Protein kinase A activates the Hippo pathway to modulate cell proliferation and differentiation

Journal Article•DOI•

Protein kinase A activates the Hippo pathway to modulate cell proliferation and differentiation

Fa-Xing Yu¹, Yifan Zhang², Hyun Woo Park¹, Jenna L. Jewell¹, Qian Chen³, Yaoting Deng², Duojia Pan³, Susan S. Taylor¹, Zhi Chun Lai², Kun-Liang Guan¹ - Show less +6 more•Institutions (3)

University of California, San Diego¹, Pennsylvania State University², Johns Hopkins University³

01 Jun 2013-Genes & Development (Cold Spring Harbor Laboratory Press)-Vol. 27, Iss: 11, pp 1223-1232

TL;DR: It is demonstrated 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 and reveals new insight into mechanisms of PKA in regulating a broad range of cellular functions.

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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.

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Journal Article•DOI•

Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer.

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Fa-Xing Yu¹, Bin Zhao², Kun-Liang Guan³•Institutions (3)

Fudan University¹, Life Sciences Institute², University of California, San Diego³

05 Nov 2015-Cell

TL;DR: The Hippo pathway regulates cell proliferation, apoptosis, and stemness in response to a wide range of extracellular and intracellular signals, including cell-cell contact, cell polarity, mechanical cues, ligands of G-protein-coupled receptors, and cellular energy status.

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1,571 citations

Cites background from "Protein kinase A activates the Hipp..."

...Since then, many indirect inhibitors for YAP/TAZ have been identified, including phosphodiesterase inhibitors rolipram and ibudilast (Yu et al., 2013a)....
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...…activate YAP/TAZ; in contrast, ligands signal through Gas-coupled GPCRs and protein kinase A (PKA), such as epinephrine and glucagon, can repress YAP/TAZ activity (Kim et al., 2013; Miller et al., 2012; Mo et al., 2012; Wennmann et al., 2014; Yu et al., 2013a; Yu et al., 2012; Zhou et al., 2015)....
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Journal Article•DOI•

Mechanisms of Hippo pathway regulation

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Zhipeng Meng¹, Toshiro Moroishi¹, Kun-Liang Guan¹•Institutions (1)

University of California, San Diego¹

01 Jan 2016-Genes & Development

TL;DR: This review focuses on recent developments in the understanding of the molecular actions of the core Hippo kinase cascade and discusses key open questions in the regulation and function of the Hippo pathway.

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Abstract: The Hippo pathway was initially identified in Drosophila melanogaster screens for tissue growth two decades ago and has been a subject extensively studied in both Drosophila and mammals in the last several years. The core of the Hippo pathway consists of a kinase cascade, transcription coactivators, and DNA-binding partners. Recent studies have expanded the Hippo pathway as a complex signaling network with >30 components. This pathway is regulated by intrinsic cell machineries, such as cell-cell contact, cell polarity, and actin cytoskeleton, as well as a wide range of signals, including cellular energy status, mechanical cues, and hormonal signals that act through G-protein-coupled receptors. The major functions of the Hippo pathway have been defined to restrict tissue growth in adults and modulate cell proliferation, differentiation, and migration in developing organs. Furthermore, dysregulation of the Hippo pathway leads to aberrant cell growth and neoplasia. In this review, we focus on recent developments in our understanding of the molecular actions of the core Hippo kinase cascade and discuss key open questions in the regulation and function of the Hippo pathway.

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1,139 citations

Journal Article•DOI•

The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment

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Randy L. Johnson¹, Georg Halder²•Institutions (2)

University of Texas MD Anderson Cancer Center¹, Katholieke Universiteit Leuven²

01 Jan 2014-Nature Reviews Drug Discovery

TL;DR: The regulation of the Hippo signalling pathway, its functions in normal homeostasis and disease, and recent progress in the identification of small-molecule pathway modulators are reviewed.

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Abstract: The Hippo signalling pathway is an emerging growth control and tumour suppressor pathway that regulates cell proliferation and stem cell functions. Defects in Hippo signalling and hyperactivation of its downstream effectors Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) contribute to the development of cancer, which suggests that pharmacological inhibition of YAP and TAZ activity may be an effective anticancer strategy. Conversely, YAP and TAZ can also have beneficial roles in stimulating tissue repair and regeneration following injury, so their activation may be therapeutically useful in these contexts. A complex network of intracellular and extracellular signalling pathways that modulate YAP and TAZ activities have recently been identified. Here, we review the regulation of the Hippo signalling pathway, its functions in normal homeostasis and disease, and recent progress in the identification of small-molecule pathway modulators.

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780 citations

Journal Article•DOI•

YAP/TAZ upstream signals and downstream responses

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Antonio Totaro¹, Tito Panciera¹, Stefano Piccolo¹•Institutions (1)

University of Padua¹

26 Jul 2018-Nature Cell Biology

TL;DR: How the transcriptional regulators YAP and TAZ integrate mechanical cues with the response to soluble signals and metabolic pathways to control multiple aspects of cell behaviour, including proliferation, cell plasticity and stemness essential for tissue regeneration is reviewed.

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Abstract: Cell behaviour is strongly influenced by physical, mechanical contacts between cells and their extracellular matrix. We review how the transcriptional regulators YAP and TAZ integrate mechanical cues with the response to soluble signals and metabolic pathways to control multiple aspects of cell behaviour, including proliferation, cell plasticity and stemness essential for tissue regeneration. Corruption of cell-environment interplay leads to aberrant YAP and TAZ activation that is instrumental for multiple diseases, including cancer.

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582 citations

Journal Article•DOI•

The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease

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Xaralabos Varelas¹•Institutions (1)

Boston University¹

15 Apr 2014-Development

TL;DR: An overview of regulatory mechanisms and important developmental processes controlled by TAZ and YAP is provided and it is outlined that TAZ/YAP activity is regulated by mechanical and cytoskeletal cues as well as by various extracellular factors.

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Abstract: Studies over the past 20 years have defined the Hippo signaling pathway as a major regulator of tissue growth and organ size. Diverse roles for the Hippo pathway have emerged, the majority of which in vertebrates are determined by the transcriptional regulators TAZ and YAP (TAZ/YAP). Key processes regulated by TAZ/YAP include the control of cell proliferation, apoptosis, movement and fate. Accurate control of the levels and localization of these factors is thus essential for early developmental events, as well as for tissue homeostasis, repair and regeneration. Recent studies have revealed that TAZ/YAP activity is regulated by mechanical and cytoskeletal cues as well as by various extracellular factors. Here, I provide an overview of these and other regulatory mechanisms and outline important developmental processes controlled by TAZ and YAP.

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539 citations

Cites background from "Protein kinase A activates the Hipp..."

...Additionally, cyclic adenosine monophosphate (cAMP), a secondary messenger downstream of Gαs-coupled receptors, acts via protein kinase A (PKA) to stimulate LATS1/ 2-mediated YAP phosphorylation to maintain high levels of cytoplasmic YAP (Kim et al., 2013; Yu et al., 2013)....
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Journal Article•DOI•

Role of YAP/TAZ in mechanotransduction

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Sirio Dupont¹, Leonardo Morsut¹, Mariaceleste Aragona¹, Elena Enzo¹, Stefano Giulitti¹, Michelangelo Cordenonsi¹, Francesca Zanconato¹, Jimmy Le Digabel², Mattia Forcato³, Silvio Bicciato³, Nicola Elvassore¹, Stefano Piccolo¹ - Show less +8 more•Institutions (3)

University of Padua¹, Paris Diderot University², University of Modena and Reggio Emilia³

09 Jun 2011-Nature

TL;DR: YAP/TAZ are identified as sensors and mediators of mechanical cues instructed by the cellular microenvironment and are functionally required for differentiation of mesenchymal stem cells induced by ECM stiffness and for survival of endothelial cells regulated by cell geometry.

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Abstract: Cells perceive their microenvironment not only through soluble signals but also through physical and mechanical cues, such as extracellular matrix (ECM) stiffness or confined adhesiveness. By mechanotransduction systems, cells translate these stimuli into biochemical signals controlling multiple aspects of cell behaviour, including growth, differentiation and cancer malignant progression, but how rigidity mechanosensing is ultimately linked to activity of nuclear transcription factors remains poorly understood. Here we report the identification of the Yorkie-homologues YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif, also known as WWTR1) as nuclear relays of mechanical signals exerted by ECM rigidity and cell shape. This regulation requires Rho GTPase activity and tension of the actomyosin cytoskeleton, but is independent of the Hippo/LATS cascade. Crucially, YAP/TAZ are functionally required for differentiation of mesenchymal stem cells induced by ECM stiffness and for survival of endothelial cells regulated by cell geometry; conversely, expression of activated YAP overrules physical constraints in dictating cell behaviour. These findings identify YAP/TAZ as sensors and mediators of mechanical cues instructed by the cellular microenvironment.

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4,120 citations

"Protein kinase A activates the Hipp..." refers background in this paper

...In addition, mechanic stress has also been shown to modulate YAP/TAZ activity (Dupont et al. 2011; Wada et al. 2011; Zhao et al. 2012)....
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...Recently, it has been reported that Rho GTPases can regulate the Hippo pathway and plays a major role from Ga12/13-coupled receptors to YAP phosphorylation (Dupont et al. 2011; Miller et al. 2012; Mo et al. 2012; Yu et al. 2012b; Zhao et al. 2012)....
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...Based on our data, NF2 is not critical for PKA to induce YAP phosphorylation because the MDA-MB-231 cells have a homozygous NF2 mutation (Dupont et al. 2011), while YAP phosphorylation is properly regulated by cAMP....
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...Formation of actin filaments or generation of cellular tension results in YAP dephosphorylation, nuclear localization, and activation (Dupont et al. 2011; Fernandez et al. 2011; Sansores-Garcia et al. 2011; Wada et al. 2011; Mo et al. 2012; Yu et al. 2012b; Zhao et al. 2012)....
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Journal Article•DOI•

Cell shape, cytoskeletal tension, and rhoa regulate stem cell lineage commitment

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Rowena McBeath¹, Dana M. Pirone¹, Celeste M. Nelson¹, Kiran Bhadriraju¹, Christopher S. Chen¹ - Show less +1 more•Institutions (1)

Johns Hopkins University School of Medicine¹

01 Apr 2004-Developmental Cell

TL;DR: It is demonstrated that cell shape regulates commitment of human mesenchymal stem cells to adipocyte or osteoblast fate and mechanical cues experienced in developmental and adult contexts, embodied by cell shape, cytoskeletal tension, and RhoA signaling, are integral to the commitment of stem cell fate.

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3,995 citations

"Protein kinase A activates the Hipp..." refers background in this paper

...Interestingly, RhoA has functions similar to those of YAP/TAZ during various cell differentiation processes (McBeath et al. 2004)....
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Journal Article•DOI•

Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control

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Bin Zhao¹, Xiaomu Wei², Weiquan Li¹, Ryan S. Udan³, Ryan S. Udan⁴, Qian Yang¹, Joungmok Kim¹, Joungmok Kim⁵, Joe Xie¹, Tsuneo Ikenoue¹, Jindan Yu¹, Li Li⁵, Li Li¹, Pan Zheng¹, Keqiang Ye⁶, Arul M. Chinnaiyan¹, Georg Halder³, Georg Halder⁴, Zhi Chun Lai², Kun-Liang Guan¹, Kun-Liang Guan⁵ - Show less +17 more•Institutions (6)

University of Michigan¹, Pennsylvania State University², Baylor College of Medicine³, University of Texas MD Anderson Cancer Center⁴, University of California, San Diego⁵, Emory University⁶

01 Nov 2007-Genes & Development

TL;DR: It is demonstrated that in mammalian cells, the transcription coactivator YAP (Yes-associated protein), is inhibited by cell density via the Hippo pathway, and YAP overexpression regulates gene expression in a manner opposite to cell density, and is able to overcome cell contact inhibition.

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Abstract: The Hippo pathway plays a key role in organ size control by regulating cell proliferation and apoptosis in Drosophila. Although recent genetic studies have shown that the Hippo pathway is regulated by the NF2 and Fat tumor suppressors, the physiological regulations of this pathway are unknown. Here we show that in mammalian cells, the transcription coactivator YAP (Yes-associated protein), is inhibited by cell density via the Hippo pathway. Phosphorylation by the Lats tumor suppressor kinase leads to cytoplasmic translocation and inactivation of the YAP oncoprotein. Furthermore, attenuation of this phosphorylation of YAP or Yorkie (Yki), the Drosophila homolog of YAP, potentiates their growth-promoting function in vivo. Moreover, YAP overexpression regulates gene expression in a manner opposite to cell density, and is able to overcome cell contact inhibition. Inhibition of YAP function restores contact inhibition in a human cancer cell line bearing deletion of Salvador (Sav), a Hippo pathway component. Interestingly, we observed that YAP protein is elevated and nuclear localized in some human liver and prostate cancers. Our observations demonstrate that YAP plays a key role in the Hippo pathway to control cell proliferation in response to cell contact.

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2,547 citations

"Protein kinase A activates the Hipp..." refers background in this paper

...Activated Lats1/2 in complex with its regulatory protein, Mob, in turn phosphorylates and inhibits YAP and TAZ, two homologous transcription coactivators (Wu et al. 2003; Chan et al. 2005; Huang et al. 2005; Callus et al. 2006; Dong et al. 2007; Zhao et al. 2007; Lei et al. 2008; Oh and Irvine 2008)....
[...]
...…Lats1/2 in complex with its regulatory protein, Mob, in turn phosphorylates and inhibits YAP and TAZ, two homologous transcription coactivators (Wu et al. 2003; Chan et al. 2005; Huang et al. 2005; Callus et al. 2006; Dong et al. 2007; Zhao et al. 2007; Lei et al. 2008; Oh and Irvine 2008)....
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...The Hippo pathway has been implicated in cell contact inhibition, as YAP/TAZ display a dramatic cell densitydependent subcellular localization and phosphorylation (Zhao et al. 2007)....
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...…of YAP/TAZ by the Lats kinases results in their cytoplasmic retention and ubiquitin-mediated degradation, which ultimately leads to inhibition of YAP/TAZ (Kanai et al. 2000; Dong et al. 2007; Zhao et al. 2007, 2010; Lei et al. 2008; Oh and Irvine 2008; Liu et al. 2010; Ren et al. 2010)....
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Journal Article•DOI•

Adipocyte differentiation from the inside out.

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Evan D. Rosen¹, Ormond A. MacDougald²•Institutions (2)

Beth Israel Deaconess Medical Center¹, University of Michigan²

01 Dec 2006-Nature Reviews Molecular Cell Biology

TL;DR: Interest in adipogenesis has increased markedly over the past few years with emphasis on the intersection between extracellular signals and the transcriptional cascade that regulates adipocyte differentiation.

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Abstract: Improved knowledge of all aspects of adipose biology will be required to counter the burgeoning epidemic of obesity. Interest in adipogenesis has increased markedly over the past few years with emphasis on the intersection between extracellular signals and the transcriptional cascade that regulates adipocyte differentiation. Many different events contribute to the commitment of a mesenchymal stem cell to the adipocyte lineage including the coordination of a complex network of transcription factors, cofactors and signalling intermediates from numerous pathways.

...read moreread less

2,363 citations

"Protein kinase A activates the Hipp..." refers background in this paper

...For instance, PKA has been shown to promote adipogenesis (Rosen and MacDougald 2006), although molecular mechanisms underlying PKA-regulated cell differentiation are not fully understood....
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Journal Article•DOI•

Elucidation of a universal size-control mechanism in Drosophila and mammals.

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Jixin Dong¹, Georg Feldmann¹, Jianbin Huang², Shian Wu¹, Nailing Zhang¹, Sarah A. Comerford², Mariana F. Gayyed¹, Robert A. Anders¹, Anirban Maitra¹, Duojia Pan¹ - Show less +6 more•Institutions (2)

Johns Hopkins University¹, University of Texas Southwestern Medical Center²

21 Sep 2007-Cell

TL;DR: It is demonstrated that a single phosphorylation site in Yki mediates the growth-suppressive output of the Hippo pathway, and that its dysregulation leads to tumorigenesis, uncovering a universal size-control mechanism in metazoan.

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2,091 citations

"Protein kinase A activates the Hipp..." refers background in this paper

...Phosphorylation of YAP/TAZ by the Lats kinases results in their cytoplasmic retention and ubiquitin-mediated degradation, which ultimately leads to inhibition of YAP/TAZ (Kanai et al. 2000; Dong et al. 2007; Zhao et al. 2007, 2010; Lei et al. 2008; Oh and Irvine 2008; Liu et al. 2010; Ren et al. 2010)....
[...]
...Activated Lats1/2 in complex with its regulatory protein, Mob, in turn phosphorylates and inhibits YAP and TAZ, two homologous transcription coactivators (Wu et al. 2003; Chan et al. 2005; Huang et al. 2005; Callus et al. 2006; Dong et al. 2007; Zhao et al. 2007; Lei et al. 2008; Oh and Irvine 2008)....
[...]
...…Lats1/2 in complex with its regulatory protein, Mob, in turn phosphorylates and inhibits YAP and TAZ, two homologous transcription coactivators (Wu et al. 2003; Chan et al. 2005; Huang et al. 2005; Callus et al. 2006; Dong et al. 2007; Zhao et al. 2007; Lei et al. 2008; Oh and Irvine 2008)....
[...]
...…of YAP/TAZ by the Lats kinases results in their cytoplasmic retention and ubiquitin-mediated degradation, which ultimately leads to inhibition of YAP/TAZ (Kanai et al. 2000; Dong et al. 2007; Zhao et al. 2007, 2010; Lei et al. 2008; Oh and Irvine 2008; Liu et al. 2010; Ren et al. 2010)....
[...]