Cortical tension promotes Kibra degradation via Par-1 DOI
Sherzod A. Tokamov,

Stephan Buiter,

Anne Ullyot

et al.

Molecular Biology of the Cell, Journal Year: 2023, Volume and Issue: 35(1)

Published: Oct. 30, 2023

The Hippo pathway is an evolutionarily conserved regulator of tissue growth. Multiple signaling components are regulated via proteolytic degradation. However, how these degradation mechanisms themselves modulated remains unexplored. Kibra a key upstream activator that promotes its own ubiquitin-mediated upon assembling complex. Here, we demonstrate complex-dependent by cortical tension. Using classical genetic, osmotic, and pharmacological manipulations myosin activity tension, show increasing tension leads to degradation, whereas decreasing increases abundance. Our study also implicates Par-1 in regulating Kib abundance downstream We manner required for tension-induced Collectively, our results reveal previously unknown molecular mechanism which affects provide novel insights into the role mechanical forces growth control.

Language: Английский

WWC proteins mediate LATS1/2 activation by Hippo kinases and imply a tumor suppression strategy DOI Creative Commons
Sixian Qi, Yuwen Zhu, Xincheng Liu

et al.

Molecular Cell, Journal Year: 2022, Volume and Issue: 82(10), P. 1850 - 1864.e7

Published: April 15, 2022

Language: Английский

Citations

67
WWC proteins–mediated compensatory mechanism restricts schwannomatosis driven by NF2 loss of function DOI Creative Commons
Xueying Wang, Rui Zhu, Pengcheng Yu

et al.

Science Advances, Journal Year: 2025, Volume and Issue: 11(4)

Published: Jan. 22, 2025

NF2-related schwannomatosis, previously known as neurofibromatosis type 2, is a genetic disorder characterized by nerve tumors due to NF2 gene mutations. Mice with Nf2 deletion develop schwannomas slowly low penetrance, hence inconvenient for preclinical studies. Here, we show that NF2, recruiting E3 ubiquitin ligases β-TrCP1/2, promotes WWC1-3 ubiquitination and degradation. In mutated cells, accumulation compensatory mechanism prevent YAP/TAZ hyperactivation rapid tumorigenesis. Accordingly, generate synthetic mouse model complete penetrance short latency concurrently deleting Wwc1/2 in Schwann cells. This closely resembles schwannomatosis patients, confirmed histological single-cell transcriptome analysis. Moreover, cell line from syngeneic tumor immune-competent mice are established. Furthermore, screen using established models has identified candidate drugs effectively suppress schwannoma progression. Hence, this work developed transplantable will facilitate both basic translational research on schwannomatosis.

Language: Английский

Citations

0
The Abelson kinase and the Nedd4 family E3 ligases co-regulate Notch trafficking to limit signaling DOI

Julio Miranda-Alban,

Nicelio Sanchez‐Luege, Fernando M. Valbuena

et al.

The Journal of Cell Biology, Journal Year: 2025, Volume and Issue: 224(6)

Published: April 4, 2025

Precise output from the conserved Notch signaling pathway governs a plethora of cellular processes and developmental transitions. Unlike other pathways that use cytoplasmic relay, cell surface receptor transduces directly to nucleus, with endocytic trafficking providing critical regulatory nodes. Here we report tyrosine kinase Abelson (Abl) facilitates internalization into late endosomes/multivesicular bodies (LEs), thereby limiting in both ligand-dependent -independent contexts. Abl phosphorylates PPxY motif within Notch, molecular target for its degradation via Nedd4 family ubiquitin ligases. We show Su(dx), member, mediates Abl-directed LE regulation PPxY, while another Nedd4Lo, contributes LEs through PPxY-dependent mechanisms. Our findings demonstrate how network posttranslational modifiers converging at cooperatively modulates ensure precision robustness functions.

Language: Английский

Citations

0
The Serine/Threonine Kinase NDR2 Regulates Integrin Signaling, Synapse Formation, and Synaptic Plasticity in the Hippocampus DOI Creative Commons
Miguel del Ángel, Atsuhiro Tsutiya,

Hussam Hayani

et al.

Journal of Neurochemistry, Journal Year: 2025, Volume and Issue: 169(6)

Published: May 29, 2025

ABSTRACT Nuclear Dbf2‐related (NDR) kinases are core components of the Hippo pathway, which controls neuronal polarity and neurite growth in central nervous system (CNS). NDR2 is principal NDR kinase mouse CNS, where it has been shown to regulate integrin‐dependent dendritic branching as well plasticity hippocampal mossy fibers. Given well‐established involvement integrins plasticity, we hypothesized that might synapse formation through integrin‐mediated mechanisms. In this study, using constitutive null mutant mice, demonstrate Ndr2 deficiency leads a reduction T788/789 phosphorylated β1 integrin expression at synaptic sites both area CA1 primary neurons vitro. This associated with decreased density conditions accompanied by reduced long‐term potentiation synapses between Schaffer collaterals/commissural fibers pyramidal cells, could be restored activation an arginine‐glycine‐aspartate‐containing peptide, mild spatial memory deficits. Together, our results suggest involved hippocampus. image

Language: Английский

Citations

0
Apical polarity and actomyosin dynamics control Kibra subcellular localization and function in Drosophila Hippo signaling DOI Creative Commons
Sherzod A. Tokamov,

Nicki Nouri,

Ashley Rich

et al.

Developmental Cell, Journal Year: 2023, Volume and Issue: 58(19), P. 1864 - 1879.e4

Published: Sept. 19, 2023

Language: Английский

Citations

6
Molecular insights of Hippo signaling in the chick developing lung DOI Creative Commons

Violina Baranauskaite Barbosa,

Pedro F. Costa-Silva,

Henrique Araújo-Silva

et al.

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Journal Year: 2022, Volume and Issue: 1866(1), P. 194904 - 194904

Published: Dec. 23, 2022

Hippo signaling pathway and its effector YAP have been recognized as an essential growth regulator during embryonic development. has studied in different contexts; nevertheless, role chick lung branching morphogenesis remains unknown. Therefore, this work aims to determine early pulmonary organogenesis the avian animal model. The current study describes spatial distribution of members by situ hybridization. Overall, their expression is comparable mammalian counterparts. Moreover, levels phosphorylated-YAP (pYAP) total revealed that active lung. Furthermore, presence pYAP cytoplasm demonstrated machinery maintained tissue. In vitro studies were performed assess branching. Lung explants treated with a YAP/TEAD complex inhibitor (verteporfin) displayed significant reduction size decreased ctgf (Hippo target gene) compared control. This approach also seems modulate key molecular players involved (sox2, sox9, axin2, gli1). Conversely, when dobutamine, upstream promotes phosphorylation, explant morphology was not severely affected. our data indicate present stages likely regulation growth.

Language: Английский

Citations

2
Cortical tension regulates Hippo signaling via Par-1-mediated Kibra degradation DOI Open Access
Sherzod A. Tokamov,

Stephan Buiter,

Anne Ullyot

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: June 18, 2023

Abstract The Hippo pathway is an evolutionarily conserved regulator of tissue growth. Multiple signaling components are regulated via proteolytic degradation. However, how these degradation mechanisms themselves modulated remains unexplored. Kibra a key upstream activator that promotes its own ubiquitin-mediated upon assembling complex. Here, we demonstrate complex-dependent by cortical tension. Using classical genetic, osmotic, and pharmacological manipulations myosin activity tension, show increasing tension leads to degradation, whereas decreasing increases abundance. Our study also implicates Par-1 in regulating Kib abundance downstream We manner required for tension-induced Collectively, our results reveal previously unknown molecular mechanism which affects provide novel insights into the role mechanical forces growth control.

Language: Английский

Citations

0
Cortical tension promotes Kibra degradation via Par-1 DOI
Sherzod A. Tokamov,

Stephan Buiter,

Anne Ullyot

et al.

Molecular Biology of the Cell, Journal Year: 2023, Volume and Issue: 35(1)

Published: Oct. 30, 2023

The Hippo pathway is an evolutionarily conserved regulator of tissue growth. Multiple signaling components are regulated via proteolytic degradation. However, how these degradation mechanisms themselves modulated remains unexplored. Kibra a key upstream activator that promotes its own ubiquitin-mediated upon assembling complex. Here, we demonstrate complex-dependent by cortical tension. Using classical genetic, osmotic, and pharmacological manipulations myosin activity tension, show increasing tension leads to degradation, whereas decreasing increases abundance. Our study also implicates Par-1 in regulating Kib abundance downstream We manner required for tension-induced Collectively, our results reveal previously unknown molecular mechanism which affects provide novel insights into the role mechanical forces growth control.

Language: Английский

Citations

0