scholarly journals Modulating F-actin organization induces organ growth by affecting the Hippo pathway

2011 ◽  
Vol 30 (12) ◽  
pp. 2325-2335 ◽  
Author(s):  
Leticia Sansores-Garcia ◽  
Wouter Bossuyt ◽  
Ken-Ichi Wada ◽  
Shigenobu Yonemura ◽  
Chunyao Tao ◽  
...  
Keyword(s):  
Hippo Pathway ◽  
Organ Growth ◽  
Actin Organization ◽  
The Hippo Pathway

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 Crumbs and the apical spectrin cytoskeleton regulate r8 cell fate in the Drosophila eye

PLoS Genetics ◽  
2021 ◽  
Vol 17 (6) ◽  
pp. e1009146
Author(s):  
Jonathan M. Pojer ◽  
Abdul Jabbar Saiful Hilmi ◽  
Shu Kondo ◽  
Kieran F. Harvey
Keyword(s):  
Cell Fate ◽  
Hippo Pathway ◽  
Green Light ◽  
Photoreceptor Cells ◽  
Organ Growth ◽  
Important Regulator ◽  
Spectrin Cytoskeleton ◽  
Fate Decision ◽  
The Hippo Pathway ◽  
Hippo Signalling

The Hippo pathway is an important regulator of organ growth and cell fate. In the R8 photoreceptor cells of the Drosophila melanogaster eye, the Hippo pathway controls the fate choice between one of two subtypes that express either the blue light-sensitive Rhodopsin 5 (Hippo inactive R8 subtype) or the green light-sensitive Rhodopsin 6 (Hippo active R8 subtype). The degree to which the mechanism of Hippo signal transduction and the proteins that mediate it are conserved in organ growth and R8 cell fate choice is currently unclear. Here, we identify Crumbs and the apical spectrin cytoskeleton as regulators of R8 cell fate. By contrast, other proteins that influence Hippo-dependent organ growth, such as the basolateral spectrin cytoskeleton and Ajuba, are dispensable for the R8 cell fate choice. Surprisingly, Crumbs promotes the Rhodopsin 5 cell fate, which is driven by Yorkie, rather than the Rhodopsin 6 cell fate, which is driven by Warts and the Hippo pathway, which contrasts with its impact on Hippo activity in organ growth. Furthermore, neither the apical spectrin cytoskeleton nor Crumbs appear to regulate the Hippo pathway through mechanisms that have been observed in growing organs. Together, these results show that only a subset of Hippo pathway proteins regulate the R8 binary cell fate decision and that aspects of Hippo signalling differ between growing organs and post-mitotic R8 cells.

scholarly journals The Hippo pathway component Wwc2 is a key regulator of embryonic development and angiogenesis in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Anke Hermann ◽  
Guangming Wu ◽  
Pavel I. Nedvetsky ◽  
Viktoria C. Brücher ◽  
Charlotte Egbring ◽  
...  
Keyword(s):  
Embryonic Development ◽  
Cell Fate ◽  
Target Genes ◽  
Hippo Pathway ◽  
Growth Control ◽  
Binding Motif ◽  
Hippo Signaling ◽  
Large Tumor ◽  
Organ Growth ◽  
The Hippo Pathway

AbstractThe WW-and-C2-domain-containing (WWC) protein family is involved in the regulation of cell differentiation, cell proliferation, and organ growth control. As upstream components of the Hippo signaling pathway, WWC proteins activate the Large tumor suppressor (LATS) kinase that in turn phosphorylates Yes-associated protein (YAP) and its paralog Transcriptional coactivator-with-PDZ-binding motif (TAZ) preventing their nuclear import and transcriptional activity. Inhibition of WWC expression leads to downregulation of the Hippo pathway, increased expression of YAP/TAZ target genes and enhanced organ growth. In mice, a ubiquitous Wwc1 knockout (KO) induces a mild neurological phenotype with no impact on embryogenesis or organ growth. In contrast, we could show here that ubiquitous deletion of Wwc2 in mice leads to early embryonic lethality. Wwc2 KO embryos display growth retardation, a disturbed placenta development, impaired vascularization, and finally embryonic death. A whole-transcriptome analysis of embryos lacking Wwc2 revealed a massive deregulation of gene expression with impact on cell fate determination, cell metabolism, and angiogenesis. Consequently, a perinatal, endothelial-specific Wwc2 KO in mice led to disturbed vessel formation and vascular hypersprouting in the retina. In summary, our data elucidate a novel role for Wwc2 as a key regulator in early embryonic development and sprouting angiogenesis in mice.

scholarly journals Crumbs and the Apical Spectrin Cytoskeleton Regulate R8 Cell Fate in the Drosophila eye

2020 ◽  
Author(s):  
Jonathan M. Pojer ◽  
Shu Kondo ◽  
Kieran F. Harvey
Keyword(s):  
Cell Fate ◽  
Hippo Pathway ◽  
Green Light ◽  
Photoreceptor Cells ◽  
Cell Fate Decision ◽  
Organ Growth ◽  
Important Regulator ◽  
Spectrin Cytoskeleton ◽  
Fate Decision ◽  
The Hippo Pathway

ABSTRACTThe Hippo pathway is an important regulator of organ growth and cell fate. In the R8 photoreceptor cells of the Drosophila melanogaster eye, the Hippo pathway controls the fate choice between one of two subtypes that express either the blue light-sensitive Rhodopsin 5 (Hippo inactive) or the green light-sensitive Rhodopsin 6 (Hippo active). The degree to which the mechanism of Hippo signal transduction and the proteins that mediate it are conserved in organ growth and R8 cell fate choice is currently unclear. Here, we identify Crumbs and the apical spectrin cytoskeleton as regulators of R8 cell fate. By contrast, other proteins that influence Hippo-dependent organ growth, such as the basolateral spectrin cytoskeleton and Ajuba, are dispensable for the R8 cell fate choice. Surprisingly, Crumbs promotes the Rhodopsin 5 cell fate, which is driven by Yorkie, rather than the Rhodopsin 6 cell fate, which is driven by Warts and the Hippo pathway, which contrasts with its impact on Hippo activity in organ growth. Furthermore, neither the apical spectrin cytoskeleton nor Crumbs regulate the Hippo pathway through mechanisms that have been reported to operate in growing organs. Together, these results show that only a subset of Hippo pathway proteins regulate the R8 binary cell fate decision and that aspects of Hippo pathway signalling appear to differ between growing organs and post-mitotic R8 cells.

scholarly journals Modulation of Yorkie activity by alternative splicing is required for developmental stability

2019 ◽  
Author(s):  
Diwas Srivastava ◽  
Marion de Toledo ◽  
Laurent Manchon ◽  
Jamal Tazi ◽  
François Juge
Keyword(s):  
Alternative Splicing ◽  
Hippo Pathway ◽  
Developmental Stability ◽  
Splicing Factor ◽  
Organ Growth ◽  
Ww Domains ◽  
Growth Promoting ◽  
Developmental Noise ◽  
The Hippo Pathway

AbstractThe mechanisms that contribute to developmental stability are barely known. Here we show that alternative splicing of yorkie (yki) is required for developmental stability in Drosophila. Yki encodes the effector of the Hippo pathway that has a central role in controlling organ growth and regeneration. We identify the splicing factor B52 as necessary for inclusion of yki alternative exon 3 that encodes one of the two WW domains of Yki protein. B52 depletion favors expression of Yki1 isoform carrying a single WW domain, and reduces growth in part through modulation of yki alternative splicing. Compared to the canonical Yki2 isoform containing two WW domains, Yki1 isoform has reduced transcriptional and growth-promoting activities, decreased binding to PPxY-containing partners, and lacks the ability to bridge two proteins containing PPxY motifs. Yet, Yki1 and Yki2 interact similarly with transcription factors and can thus compete in vivo. Strikingly, flies deprived from Yki1 isoform exhibit increased fluctuating wing asymmetry, a signal of increased developmental noise. Our results identify yki alternative splicing as a new level of control of the Hippo pathway and provide the first experimental evidence that alternative splicing participates in developmental robustness.

scholarly journals Yap regulates glucose utilization and sustains nucleotide synthesis to enable organ growth

2018 ◽  
Author(s):  
Andrew G. Cox ◽  
Allison Tsomides ◽  
Dean Yimlamai ◽  
Katie L. Hwang ◽  
Joel Miesfeld ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Target Genes ◽  
Glucose Transporter ◽  
Hippo Pathway ◽  
Nucleotide Synthesis ◽  
Nucleotide Biosynthesis ◽  
Liver Growth ◽  
Organ Growth ◽  
Evolutionarily Conserved ◽  
The Hippo Pathway

AbstractThe Hippo pathway and its nuclear effector Yap regulate organ size and cancer formation. While many modulators of Hippo activity have been identified, little is known about the Yap target genes that mediate these growth effects. Here, we show that yap-/- mutant zebrafish exhibit defects in hepatic progenitor potential and liver growth due to impaired glucose transport and nucleotide biosynthesis: transcriptomic and metabolomic analyses reveal that Yap regulates expression of glucose transporter glut1, causing decreased glucose uptake and use for nucleotide biosynthesis in yap-/- mutants, and impaired glucose tolerance in adults. Nucleotide supplementation improved Yap-deficiency phenotypes, indicating functional importance of glucose-fuelled nucleotide biosynthesis. Yap-regulated Glut1 expression and glucose uptake are conserved in mammals, suggesting that stimulation of anabolic glucose metabolism is an evolutionarily conserved mechanism by which the Hippo pathway controls organ growth. Together, our results reveal a central role for Hippo signalling in metabolic homeostasis.

scholarly journals The Hippo pathway: key interaction and catalytic domains in organ growth control, stem cell self-renewal and tissue regeneration

2012 ◽  
Vol 53 ◽  
pp. 111-127 ◽  
Author(s):  
Claire Cherrett ◽  
Makoto Furutani-Seiki ◽  
Stefan Bagby
Keyword(s):  
Stem Cell ◽  
Hippo Pathway ◽  
Growth Control ◽  
Activation Function ◽  
Binding Motif ◽  
Self Renewal ◽  
Organ Growth ◽  
Co Activation ◽  
Multiple Processes ◽  
The Hippo Pathway

The Hippo pathway is a conserved pathway that interconnects with several other pathways to regulate organ growth, tissue homoeostasis and regeneration, and stem cell self-renewal. This pathway is unique in its capacity to orchestrate multiple processes, from sensing to execution, necessary for organ expansion. Activation of the Hippo pathway core kinase cassette leads to cytoplasmic sequestration of the nuclear effectors YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), consequently disabling their transcriptional co-activation function. Components upstream of the core kinase cassette have not been well understood, especially in vertebrates, but are gradually being elucidated and include cell polarity and cell adhesion proteins.

scholarly journals WTS-1/LATS regulates endocytic recycling by restraining F-actin assembly in a synergistic manner

2021 ◽  
Author(s):  
Hanchong Zhang ◽  
Zihang Cheng ◽  
Wenbo Li ◽  
Jie Hu ◽  
Linyue Zhao ◽  
...  
Keyword(s):  
Actin Polymerization ◽  
Hippo Pathway ◽  
Actin Assembly ◽  
Core Component ◽  
Endocytic Recycling ◽  
Actin Organization ◽  
C Elegans ◽  
The Hippo Pathway ◽  
Homeostatic Mechanisms

The disruption of endosomal actin architecture negatively affects endocytic recycling. However, the underlying homeostatic mechanisms that regulate actin organization during recycling remain unclear. In this study, we identified a synergistic endosomal actin assembly restricting mechanism in C. elegans involving WTS-1/LATS kinase, which is a core component of the Hippo pathway. WTS-1 resides on the sorting endosomes and colocalizes with the actin polymerization regulator PTRN-1/CAMSAPs. We observed an increase in PTRN-1-labeled structures in WTS-1-deficient cells, indicating that WTS-1 can limit the endosomal localization of PTRN-1. Accordingly, the actin overaccumulation phenotype in WTS-1-depleted cells was mitigated by the associated PTRN-1 loss. We further demonstrated that recycling defects and actin overaccumulation in WTS-1-deficient cells were reduced by the overexpression of constitutively active UNC-60A/cofilin(S3A), which aligns with the role of LATS as a positive regulator of cofilin activity. Altogether, our data confirmed previous findings, and we proposed an additional model: WTS-1 acts alongside the UNC-60A/cofilin-mediated actin disassembly to restrict the assembly of endosomal F-actin by curbing PTRN-1 dwelling on endosomes, preserving recycling transport.

scholarly journals TRIP6 is required for tension at adherens junctions

2020 ◽  
Author(s):  
Srividya Venkatramanan ◽  
Consuelo Ibar ◽  
Kenneth D. Irvine
Keyword(s):  
Myosin Light Chain ◽  
Adherens Junctions ◽  
Hippo Pathway ◽  
Focal Adhesions ◽  
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 recruitment of Vinculin and VASP to adherens junctions. Knockdown of TRIP6 or Vinculin, but not of LIMD1, also influences the localization of phosphorylated myosin light chain and F-actin. In TRIP6 knockdown cells actin stress fibers are lost apically but increased basally, and there is a corresponding increase in recruitment of Vinculin and VASP to basal focal adhesions. These 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 Modulation of the Hippo pathway and organ growth by RNA processing proteins

2018 ◽  
Vol 115 (42) ◽  
pp. 10684-10689 ◽  
Author(s):  
Jana Mach ◽  
Mardelle Atkins ◽  
Kathleen M. Gajewski ◽  
Violaine Mottier-Pavie ◽  
Leticia Sansores-Garcia ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Biology ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Hippo Pathway ◽  
Apical Cell ◽  
Ectopic Expression ◽  
Tissue Growth ◽  
Organ Growth ◽  
The Hippo Pathway

The Hippo tumor-suppressor pathway regulates organ growth, cell proliferation, and stem cell biology. Defects in Hippo signaling and hyperactivation of its downstream effectors—Yorkie (Yki) in Drosophila and YAP/TAZ in mammals—result in progenitor cell expansion and overgrowth of multiple organs and contribute to cancer development. Deciphering the mechanisms that regulate the activity of the Hippo pathway is key to understanding its function and for therapeutic targeting. However, although the Hippo kinase cascade and several other upstream inputs have been identified, the mechanisms that regulate Yki/YAP/TAZ activity are still incompletely understood. To identify new regulators of Yki activity, we screened in Drosophila for suppressors of tissue overgrowth and Yki activation caused by overexpression of atypical protein kinase C (aPKC), a member of the apical cell polarity complex. In this screen, we identified mutations in the heterogeneous nuclear ribonucleoprotein Hrb27C that strongly suppressed the tissue defects induced by ectopic expression of aPKC. Hrb27C was required for aPKC-induced tissue growth and Yki target gene expression but did not affect general gene expression. Genetic and biochemical experiments showed that Hrb27C affects Yki phosphorylation. Other RNA-binding proteins known to interact with Hrb27C for mRNA transport in oocytes were also required for normal Yki activity, although they suppressed Yki output. Based on the known functions of Hrb27C, we conclude that Hrb27C-mediated control of mRNA splicing, localization, or translation is essential for coordinated activity of the Hippo pathway.

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