Cellular Compartmentalization as a Physical Regulatory Mechanism of Signaling Pathways DOI Creative Commons
Ahmed Naser Fayad,

Diego Mazo-Durán,

David G. Míguez

et al.

Biophysica, Journal Year: 2024, Volume and Issue: 4(4), P. 634 - 650

Published: Dec. 10, 2024

Cells compartmentalize biochemical processes using physical barriers in the form of membranes. Eukaryotes have a wide diversity membrane-based compartments that can be used this context, with main ones being extracellular membrane, which separates inside from outside cell, and nuclear nucleus cytoplasm. The membrane not only isolates protects DNA transcription replication other are occurring cytoplasm but also has an active role regulation cellular signaling. TGF-β pathway is one most important conserved signaling cascades, it achieves compartmentalization well-tuned balance between import export rates inactive forms key proteins. Thus, serves as additional regulatory mechanism, physically isolating factors their targets, influencing dynamics strength signal transduction. This contribution focuses on biophysical layer regulation, to illustrate molecular mechanisms underlying process, well biological consequences compartmentalization. We introduce simplified mathematical formulation for studying process generalized approach.

Language: Английский

AThe M-motif: a potential new class of non-conventional NLS in TAZ/YAP and other cellular and viral proteins that inhibits classic protein import DOI Creative Commons

Michael Kofler,

Shruthi Venugopal,

Gordon N. Gill

et al.

iScience, Journal Year: 2025, Volume and Issue: 28(4), P. 112105 - 112105

Published: Feb. 26, 2025

Language: Английский

Citations

1
Dynamic structure and function of nuclear pore protein complex: Potential roles of lipid and lamins regulated nuclear membrane curvature DOI

Kunpeng Wu,

Zhen Yan,

Xiao-Xi Zhuang

et al.

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: unknown, P. 144104 - 144104

Published: May 1, 2025

Language: Английский

Citations

1
PPARα regulates YAP protein levels and activity by affecting its ubiquitination modification DOI Creative Commons

Wenhong Zhou,

Shuaishuai Zhang, Qianming Chen

et al.

BMC Biology, Journal Year: 2025, Volume and Issue: 23(1)

Published: Feb. 28, 2025

Peroxisome proliferator-activated receptor α (PPARα) plays a crucial role in liver physiological and pathological processes. Yes-associated protein (YAP) is key effector regulating cell growth organ size. Ubiquitination known to modulate YAP expression, stability, nuclear localization. Our previous study demonstrated that PPARα activation promotes hepatomegaly regeneration via activation. However, the underlying molecular mechanisms by which regulates are unclear. In this study, was activated classical agonist WY-14643, its effects on ubiquitination were examined using plasmid transfection immunoprecipitation. The of further investigated through mutant plasmids, gene knockdown, immunofluorescence staining. mRNA expression measured qRT-PCR western blotting. results upregulated levels enhanced activity, while reducing overall ubiquitination. Specifically, inhibited K48-linked promoting K63-linked YAP. Mutations at K252, K321, K497 residues markedly reduced capacity facilitate translocation. Furthermore, knockdown E3 ligase TRAF6 abolished PPARα-induced upregulation downstream target genes. These findings highlight pivotal activation, providing novel insights for future studies post-translational regulation

Language: Английский

Citations

0
Phosphate-dependent nuclear export via a non-classical NES class recognized by exportin Msn5 DOI Creative Commons
Ho Yee Joyce Fung, Sanraj R. Mittal, Ashley B. Niesman

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 16, 2025

Gene expression in response to environmental stimuli is dependent on nuclear localization of key signaling components, which can be tightly regulated by phosphorylation. This exemplified the phosphate-sensing transcription factor Pho4, requires phosphorylation for export yeast exportin Msn5. Here, we present a high resolution cryogenic-electron microscopy structure showing phosphorylated 35-residue signal binds concave surface Msn5 through two Pho4 phospho-serines that align with basic patches. These findings characterize mechanism phosphate-specific recognition mediated non-classical distinct from Exportin-1. Furthermore, discovery unliganded autoinhibited explains positive cooperativity Pho4/Ran-binding and proposes Pho4's release cytoplasm. advance our understanding diversity signals drive how cargo crucial regulating transport controlling cellular pathways. Structural biochemical studies Fung et al. explain Msn5, revealing recognized XPO1.

Language: Английский

Citations

0
YAP/TAZ: An Epitome of Tumorigenesis DOI
Soumya Mukherjee,

Emily A Warden,

Jianmin Zhang

et al.

Cancer Letters, Journal Year: 2025, Volume and Issue: unknown, P. 217806 - 217806

Published: May 1, 2025

Language: Английский

Citations

0
Spatiotemporal distribution of YAP and importin-β in nucleus and cytosol after wounding of adjacent cells DOI

Boyuan Xiao,

Saori SASAKI,

Naoki Takeishi

et al.

In Vitro Cellular & Developmental Biology - Animal, Journal Year: 2025, Volume and Issue: unknown

Published: May 29, 2025

Language: Английский

Citations

0
CDK9 Inhibition by Dinaciclib Is a Therapeutic Vulnerability in Epithelioid Hemangioendothelioma DOI
Ajaybabu V. Pobbati, Ashley Burtscher, Nandini Rajaram Siva

et al.

Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 30(18), P. 4179 - 4189

Published: July 25, 2024

There are no effective treatment options for patients with aggressive epithelioid hemangioendothelioma (EHE) driven by the TAZ-CAMTA1 (TC) fusion gene. Here, we aimed to understand regulation of TC using pharmacologic tools and identify vulnerabilities that can potentially be exploited EHE.

Language: Английский

Citations

3
Characterization of tumor endothelial cells (TEC) in gastric cancer and development of a TEC-based risk signature using single-cell RNA-seq and bulk RNA-seq data DOI Creative Commons
Meng Fan, Xiaofei Xu,

Yu Hu

et al.

Aging, Journal Year: 2024, Volume and Issue: 16(12), P. 10252 - 10270

Published: June 12, 2024

Tumor endothelial cells (TECs) are essential participants in tumorigenesis. This study is focused on elucidating the TEC traits gastric cancer (GC) and constructing a prognostic risk model to predict clinical outcome of GC patients.

Language: Английский

Citations

2
The TLK1>Nek1 Axis Promotes Nuclear Retention and Activation of YAP with Implications for CRPC DOI Open Access
Damilola Olatunde, Arrigo De Benedetti

Published: July 22, 2024

Despite some advances in controlling progression of Prostate Cancer (PCa) that is refractory to the use ADT/ARSI, most patients eventually succumb disease, and there a pressing need understand mechanisms lead development CRPC. A common mechanism ability integrate AR signals from vanishing levels testosterone, with frequent participation YAP as coactivator, pointing deregulation Hippo pathway major determinant. We have recently shown post-transcriptionally activated via TLK1>NEK1 axis by stabilizing phosphorylation at Y407. are now solidifying this work showing that: 1) The Y407 critical for retention/partition nuclei, J54 (TLK1i) reverses along YAP407 dephosphorylation. 2) That enhanced degradation (cytoplasmic) increased counteracting its Enzalutamide-induced accumulation. 3) basis all these effects, including nuclear retention, can be explained stronger association pYAP-Y407 transcriptional co-activators, TEAD1. 4) demonstrate ChIP GFP-YAP-wt, but hardly GFP-YAP-Y407F mutant, promoters typical ARE- TEAD1-driven genes readily detected becomes displaced after treatment J54. 5) While xenografts LNCaP cells show rapid regression following ARSI+J54, VCaP model, driven TMPRSS2-ERG oncogenic translocation, tumors initially respond well combination subsequently recur, despite continuous suppression pNek1-T141 pYAP-Y407. This suggests an alternative parallel CRPC long-term, may separate observed ENZ-driven deregulation, although clearly gene targets like PD-L1, found accumulate prolonged ENZ treatment, still suppressed concomitant addition

Language: Английский

Citations

2
A feedback loop between plakophilin 4 and YAP signaling regulates keratinocyte differentiation DOI Creative Commons
Lisa Müller, Tony Gutschner, Meçhthild Hatzfeld

et al.

iScience, Journal Year: 2024, Volume and Issue: 27(9), P. 110762 - 110762

Published: Aug. 19, 2024

The Hippo signaling pathway is an important regulator of organ growth and differentiation, its deregulation contributes to the development cancer. activity downstream targets YAP/TAZ depends on adherens junctions. Plakophilin 4 (PKP4) a cell-type specific junction protein expressed in proliferating cells epidermis. Here, we show that PKP4 diminishes proliferation as well differentiation. Depletion increased but at same time induced premature epidermal interacted with several components, including transcriptional co-activators YAP/TAZ, promoted nuclear YAP localization target gene expression. In differentiated keratinocytes, recruited LATS cell junctions where transcriptionally inactive. depletion, other hand, reduced levels keratinocyte adhesion indicative feedback mechanism controlling adhesion, proliferation, differentiation by balancing functions.

Language: Английский

Citations

2