scholarly journals Spectrin regulates Hippo signaling by modulating cortical actomyosin activity

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Hua Deng ◽  
Wei Wang ◽  
Jianzhong Yu ◽  
Yonggang Zheng ◽  
Yun Qing ◽  
...  
Keyword(s):  
Hippo Pathway ◽  
Myosin Ii ◽  
Tissue Growth ◽  
Hippo Signaling ◽  
Upstream Regulator ◽  
Kinase Cascade ◽  
Cytoskeletal Tension ◽  
Living Tissues ◽  
The Hippo Pathway ◽  
Upstream Regulators

The Hippo pathway controls tissue growth through a core kinase cascade that impinges on the transcription of growth-regulatory genes. Understanding how this pathway is regulated in development remains a major challenge. Recent studies suggested that Hippo signaling can be modulated by cytoskeletal tension through a Rok-myosin II pathway. How cytoskeletal tension is regulated or its relationship to the other known upstream regulators of the Hippo pathway remains poorly defined. In this study, we identify spectrin, a contractile protein at the cytoskeleton-membrane interface, as an upstream regulator of the Hippo signaling pathway. We show that, in contrast to canonical upstream regulators such as Crumbs, Kibra, Expanded, and Merlin, spectrin regulates Hippo signaling in a distinct way by modulating cortical actomyosin activity through non-muscle myosin II. These results uncover an essential mediator of Hippo signaling by cytoskeleton tension, providing a new entry point to dissecting how mechanical signals regulate Hippo signaling in living tissues.

scholarly journals SAV1 promotes Hippo kinase activation through antagonizing the PP2A phosphatase STRIPAK

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Sung Jun Bae ◽  
Lisheng Ni ◽  
Adam Osinski ◽  
Diana R Tomchick ◽  
Chad A Brautigam ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Hippo Pathway ◽  
Tissue Growth ◽  
Activation Loop ◽  
Hippo Signaling ◽  
Ww Domains ◽  
Kinase Activation ◽  
Genetic Ablation ◽  
Kinase Cascade ◽  
The Hippo Pathway

The Hippo pathway controls tissue growth and homeostasis through a central MST-LATS kinase cascade. The scaffold protein SAV1 promotes the activation of this kinase cascade, but the molecular mechanisms remain unknown. Here, we discover SAV1-mediated inhibition of the PP2A complex STRIPAKSLMAP as a key mechanism of MST1/2 activation. SLMAP binding to autophosphorylated MST2 linker recruits STRIPAK and promotes PP2A-mediated dephosphorylation of MST2 at the activation loop. Our structural and biochemical studies reveal that SAV1 and MST2 heterodimerize through their SARAH domains. Two SAV1–MST2 heterodimers further dimerize through SAV1 WW domains to form a heterotetramer, in which MST2 undergoes trans-autophosphorylation. SAV1 directly binds to STRIPAK and inhibits its phosphatase activity, protecting MST2 activation-loop phosphorylation. Genetic ablation of SLMAP in human cells leads to spontaneous activation of the Hippo pathway and alleviates the need for SAV1 in Hippo signaling. Thus, SAV1 promotes Hippo activation through counteracting the STRIPAKSLMAP PP2A phosphatase complex.

scholarly journals Activation mechanisms of the Hippo kinase signaling cascade

2018 ◽  
Vol 38 (4) ◽  
Author(s):  
Sung Jun Bae ◽  
Xuelian Luo
Keyword(s):  
Hippo Pathway ◽  
Adaptor Proteins ◽  
Tissue Growth ◽  
Fine Tuning ◽  
Hippo Signaling ◽  
Kinase Activation ◽  
The Core ◽  
Activation Mechanisms ◽  
Kinase Cascade ◽  
The Hippo Pathway

First discovered two decades ago through genetic screens in Drosophila, the Hippo pathway has been shown to be conserved in metazoans and controls organ size and tissue homeostasis through regulating the balance between cell proliferation and apoptosis. Dysregulation of the Hippo pathway leads to aberrant tissue growth and tumorigenesis. Extensive studies in Drosophila and mammals have identified the core components of Hippo signaling, which form a central kinase cascade to ultimately control gene expression. Here, we review recent structural, biochemical, and cellular studies that have revealed intricate phosphorylation-dependent mechanisms in regulating the formation and activation of the core kinase complex in the Hippo pathway. These studies have established the dimerization-mediated activation of the Hippo kinase (mammalian Ste20-like 1 and 2 (MST1/2) in mammals), the dynamic scaffolding and allosteric roles of adaptor proteins in downstream kinase activation, and the importance of multisite linker autophosphorylation by Hippo and MST1/2 in fine-tuning the signaling strength and robustness of the Hippo pathway. We highlight the gaps in our knowledge in this field that will require further mechanistic studies.

scholarly journals Hippo signaling in the kidney: the good and the bad

2016 ◽  
Vol 311 (2) ◽  
pp. F241-F248 ◽  
Author(s):  
Jenny S. Wong ◽  
Kristin Meliambro ◽  
Justina Ray ◽  
Kirk N. Campbell
Keyword(s):  
Embryonic Development ◽  
Current Knowledge ◽  
Hippo Pathway ◽  
Hippo Signaling ◽  
Filtration Barrier ◽  
Signaling Axis ◽  
Kinase Cascade ◽  
Barrier Regulation ◽  
Renal Tubular ◽  
The Hippo Pathway

The Hippo signaling pathway is an evolutionarily conserved kinase cascade, playing multiple roles in embryonic development that controls organ size, cell proliferation, and apoptosis. At the center of this network lie the Hippo kinase target and downstream pathway effector Yes-associated protein (YAP) and its paralog TAZ. In its phosphorylated form, cytoplasmic YAP is sequestered in an inactive state. When it is dephosphorylated, YAP, a potent oncogene, is activated and relocates to the nucleus to interact with a number of transcription factors and signaling regulators that promote cell growth, differentiation, and survival. The identification of YAP activation in human cancers has made it an attractive target for chemotherapeutic drug development. Little is known to date about the function of the Hippo pathway in the kidney, but that is rapidly changing. Recent studies have shed light on the role of Hippo-YAP signaling in glomerular and lower urinary tract embryonic development, maintenance of podocyte homeostasis, the integrity of the glomerular filtration barrier, regulation of renal tubular cyst growth, renal epithelial injury in diabetes, and renal fibrogenesis. This review summarizes the current knowledge of the Hippo-YAP signaling axis in the kidney under normal and disease conditions.

scholarly journals Hippo and rassf1a Pathways: A Growing Affair

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Francesca Fausti ◽  
Silvia Di Agostino ◽  
Andrea Sacconi ◽  
Sabrina Strano ◽  
Giovanni Blandino
Keyword(s):  
Developmental Biology ◽  
Tissue Regeneration ◽  
Target Genes ◽  
Hippo Pathway ◽  
Hippo Signaling ◽  
Transcriptional Coactivator ◽  
Pathway Activity ◽  
Kinase Cascade ◽  
The Hippo Pathway ◽  
The Impact

First discovered in Drosophila, the Hippo pathway regulates the size and shape of organ development. Its discovery and study have helped to address longstanding questions in developmental biology. Central to this pathway is a kinase cascade leading from the tumor suppressor Hippo (Mst1 and Mst2 in mammals) to the Yki protein (YAP and TAZ in mammals), a transcriptional coactivator of target genes involved in cell proliferation, survival, and apoptosis. A dysfunction of the Hippo pathway activity is frequently detected in human cancers. Recent studies have highlighted that the Hippo pathway may play an important role in tissue homoeostasis through the regulation of stem cells, cell differentiation, and tissue regeneration. Recently, the impact of RASSF proteins on Hippo signaling potentiating its proapoptotic activity has been addressed, thus, providing further evidence for Hippo's key role in mammalian tumorigenesis as well as other important diseases.

scholarly journals TRIP6 is required for tension at adherens junctions

2021 ◽  
Vol 134 (6) ◽  
pp. jcs247866
Author(s):  
Srividya Venkatramanan ◽  
Consuelo Ibar ◽  
Kenneth D. Irvine
Keyword(s):  
Adherens Junctions ◽  
Hippo Pathway ◽  
Focal Adhesions ◽  
Stress Fibers ◽  
Hippo Signaling ◽  
Organ Growth ◽  
Dependent Inhibition ◽  
Cytoskeletal Tension ◽  
The Hippo Pathway ◽  
The Relationship

ABSTRACTHippo signaling mediates influences of cytoskeletal tension on organ growth. TRIP6 and LIMD1 have each been identified as being required for tension-dependent inhibition of the Hippo pathway LATS kinases and their recruitment to adherens junctions, but the relationship between TRIP6 and LIMD1 was unknown. Using siRNA-mediated gene knockdown, we show that TRIP6 is required for LIMD1 localization to adherens junctions, whereas LIMD1 is not required for TRIP6 localization. TRIP6, but not LIMD1, is also required for the recruitment of vinculin and VASP to adherens junctions. Knockdown of TRIP6 or vinculin, but not of LIMD1, also influences the localization of myosin and F-actin. In TRIP6 knockdown cells, actin stress fibers are lost apically but increased basally, and there is a corresponding increase in the recruitment of vinculin and VASP to basal focal adhesions. Our observations identify a role for TRIP6 in organizing F-actin and maintaining tension at adherens junctions that could account for its influence on LIMD1 and LATS. They also suggest that focal adhesions and adherens junctions compete for key proteins needed to maintain attachments to contractile F-actin.

scholarly journals Yorkie-independent negative feedback couples Hippo pathway activation with Kibra degradation

2020 ◽  
Author(s):  
Sherzod A. Tokamov ◽  
Ting Su ◽  
Anne Ullyot ◽  
Richard G. Fehon
Keyword(s):  
Negative Feedback ◽  
Feedback Loop ◽  
Hippo Pathway ◽  
Tissue Growth ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway ◽  
The Core ◽  
Pathway Activation ◽  
The Hippo Pathway ◽  
Transcriptional Output

AbstractThe Hippo signaling pathway regulates tissue growth in many animals. Multiple upstream components are known to promote Hippo pathway activity, but the organization of these different inputs, the degree of crosstalk between them, and whether they are regulated in a distinct manner is not well understood. Kibra activates the Hippo pathway by recruiting the core Hippo kinase cassette to the apical cortex. Here we show that the Hippo pathway downregulates Kibra levels independently of Yorkie-mediated transcriptional output. We find that the Hippo pathway promotes Kibra degradation via SCFSlimb-mediated ubiquitination, that this effect requires the core kinases Hippo and Warts, and that this mechanism functions independently of other upstream Hippo pathway activators including Crumbs and Expanded. Moreover, Kibra degradation appears patterned across tissue. We propose that Kibra degradation by the Hippo pathway serves as a negative feedback loop to tightly control Kibra-mediated Hippo pathway activation and ensure optimally scaled and patterned tissue growth.

scholarly journals The Hippo Pathway: Biology and Pathophysiology

2019 ◽  
Vol 88 (1) ◽  
pp. 577-604 ◽  
Author(s):  
Shenghong Ma ◽  
Zhipeng Meng ◽  
Rui Chen ◽  
Kun-Liang Guan
Keyword(s):  
Molecular Mechanisms ◽  
Hippo Pathway ◽  
Size Control ◽  
Tissue Growth ◽  
Cell Contact ◽  
Energy Status ◽  
Downstream Effectors ◽  
Kinase Cascade ◽  
Fate Decision ◽  
The Hippo Pathway

The Hippo pathway was initially discovered in Drosophila melanogaster as a key regulator of tissue growth. It is an evolutionarily conserved signaling cascade regulating numerous biological processes, including cell growth and fate decision, organ size control, and regeneration. The core of the Hippo pathway in mammals consists of a kinase cascade, MST1/2 and LATS1/2, as well as downstream effectors, transcriptional coactivators YAP and TAZ. These core components of the Hippo pathway control transcriptional programs involved in cell proliferation, survival, mobility, stemness, and differentiation. The Hippo pathway is tightly regulated by both intrinsic and extrinsic signals, such as mechanical force, cell–cell contact, polarity, energy status, stress, and many diffusible hormonal factors, the majority of which act through G protein–coupled receptors. Here, we review the current understanding of molecular mechanisms by which signals regulate the Hippo pathway with an emphasis on mechanotransduction and the effects of this pathway on basic biology and human diseases.

scholarly journals Poly(rC)-Binding Protein 2 Regulates Hippo Signaling To Control Growth in Breast Epithelial Cells

2016 ◽  
Vol 36 (16) ◽  
pp. 2121-2131 ◽  
Author(s):  
Fengmin Li ◽  
Kimberly Z. Bullough ◽  
Ajay A. Vashisht ◽  
James A. Wohlschlegel ◽  
Caroline C. Philpott
Keyword(s):  
Epithelial Cells ◽  
Target Genes ◽  
Hippo Pathway ◽  
Control Cell ◽  
Tissue Growth ◽  
Hippo Signaling ◽  
Breast Epithelial Cells ◽  
Mouse Tissues ◽  
Kinase Cascade ◽  
Breast Epithelial

Poly(rC)-binding proteins (PCBPs) are multifunctional adapters that mediate interactions between nucleic acids, iron cofactors, and other proteins, affecting the fates and activities of the components of these interactions. Here, we show that PCBP2 forms a complex with the Hippo pathway components Salvador (Sav1), Mst1, Mst2, and Lats1 in human cells and mouse tissues. Hippo is a kinase cascade that functions to phosphorylate and inactivate the transcriptional coactivators YAP and TAZ, which control cell growth and proliferation. PCBP2 specifically interacts with the scaffold protein Sav1 and prevents proteolytic cleavage of the Mst1 kinase, resulting in increased signaling through Hippo and suppressed activity of YAP and TAZ. Human breast epithelial cells lacking PCBP2 exhibit impaired proteasomal degradation of TAZ. They accumulate TAZ in both the nucleus and the cytosol, increase expression of YAP and TAZ connective tissue growth factor (CTGF) and Cyr61 target genes, and exhibit anchorage-independent growth. Thus, PCBP2 can function as a component of the Hippo complex, enhancing signaling, suppressing activity of YAP and TAZ, and altering the growth characteristics of cells.

scholarly journals Nerfin-1 represses transcriptional output of Hippo signaling in cell competition

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Pengfei Guo ◽  
Chang-Hyun Lee ◽  
Huiyan Lei ◽  
Yonggang Zheng ◽  
Katiuska Daniela Pulgar Prieto ◽  
...  
Keyword(s):  
Dna Binding ◽  
Hippo Pathway ◽  
Ectopic Expression ◽  
Tissue Growth ◽  
Hippo Signaling ◽  
Dependent Manner ◽  
Cell Competition ◽  
Regulatory Mode ◽  
The Hippo Pathway ◽  
Transcriptional Output

The Hippo tumor suppressor pathway regulates tissue growth in Drosophila by restricting the activity of the transcriptional coactivator Yorkie (Yki), which normally complexes with the TEF/TEAD family DNA-binding transcription factor Scalloped (Sd) to drive the expression of growth-promoting genes. Given its pivotal role as a central hub in mediating the transcriptional output of Hippo signaling, there is great interest in understanding the molecular regulation of the Sd-Yki complex. In this study, we identify Nerfin-1 as a transcriptional repressor that antagonizes the activity of the Sd-Yki complex by binding to the TEA DNA-binding domain of Sd. Consistent with its biochemical function, ectopic expression of Nerfin-1 results in tissue undergrowth in an Sd-dependent manner. Conversely, loss of Nerfin-1 enhances the ability of winner cells to eliminate loser cells in multiple scenarios of cell competition. We further show that INSM1, the mammalian ortholog of Nerfin-1, plays a conserved role in repressing the activity of the TEAD-YAP complex. These findings reveal a novel regulatory mode converging on the transcriptional output of the Hippo pathway that may be exploited for modulating the YAP oncoprotein in cancer and regenerative medicine.

scholarly journals The miRNA bantam regulates growth and tumorigenesis by repressing the cell cycle regulator tribbles

2019 ◽  
Vol 2 (4) ◽  
pp. e201900381 ◽  
Author(s):  
Stephan U Gerlach ◽  
Moritz Sander ◽  
Shilin Song ◽  
Héctor Herranz
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Target Genes ◽  
Hippo Pathway ◽  
Growth Control ◽  
Tissue Growth ◽  
Tumor Formation ◽  
Hippo Signaling ◽  
Cell Cycle Regulators ◽  
The Hippo Pathway

One of the fundamental issues in biology is understanding how organ size is controlled. Tissue growth has to be carefully regulated to generate well-functioning organs, and defects in growth control can result in tumor formation. The Hippo signaling pathway is a universal growth regulator and has been implicated in cancer. In Drosophila, the Hippo pathway acts through the miRNA bantam to regulate cell proliferation and apoptosis. Even though the bantam targets regulating apoptosis have been determined, the target genes controlling proliferation have not been identified thus far. In this study, we identify the gene tribbles as a direct bantam target gene. Tribbles limits cell proliferation by suppressing G2/M transition. We show that tribbles regulation by bantam is central in controlling tissue growth and tumorigenesis. We expand our study to other cell cycle regulators and show that deregulated G2/M transition can collaborate with oncogene activation driving tumor formation.

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