Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling DOI Creative Commons
Samuel C. Griffiths, Jia Tan, Armin Wagner

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2021, Volume and Issue: unknown

Published: July 26, 2021

Abstract The receptor tyrosine kinase ROR2 mediates noncanonical WNT5A signaling to orchestrate tissue morphogenetic processes, and dysfunction of the pathway causes Robinow syndrome, Brachydactyly B metastatic diseases. domain(s) mechanisms required for function, however, remain unclear. We solved crystal structure extracellular cysteine-rich (CRD) Kringle (Kr) domains found that, unlike other CRDs, CRD lacks signature hydrophobic pocket that binds lipids/lipid-modified proteins, such as WNTs, suggesting a novel mechanism ligand reception. Functionally, we showed CRD, but not domains, is minimally sufficient promote signaling, mutations in adjacent Kr impair secretion function. Moreover, using function-activating -perturbing antibodies against Frizzled (FZ) family WNT receptors, demonstrate involvement FZ WNT5A-ROR signaling. Thus, acts via its potentiate function super-complex includes transduce signals.

Language: Английский

Identification of Wnt-5a Receptors Important in Diabetic and Non-Diabetic Corneal Epithelial Wound Healing DOI Creative Commons
Ruchi Shah,

Cynthia Amador,

Adam J. Poe

et al.

Investigative Ophthalmology & Visual Science, Journal Year: 2025, Volume and Issue: 66(2), P. 64 - 64

Published: Feb. 25, 2025

Purpose: Persistent epithelial alterations such as delayed wound healing are a key feature of diabetic corneal disease. Previously, we reported that epigenetic changes in the cornea led to suppression Wnt-5a, and addition Wnt-5a accelerated healing. In this study, set determine which Wnt receptor(s) mediated induced stimulation Methods: Human limbal cells (LECs) were isolated from postmortem non-diabetic donor eyes for single-cell RNA sequencing (scRNA-seq) DNA methylation analysis. These analyses validated by qRT-PCR, western blot, or immunostaining tissue sections. Cultured primary LECs transfected with small interfering (siRNA) specific receptors evaluate their role scratch presence absence 200 ng/mL Wnt-5a. Results: Single-cell analysis revealed differential gene expression receptors, ROR2, MCAM, FZD5, FZD6, FZD7. arrays showed hypomethylation ROR2 promoter versus 41.3% (**P < 0.01) resulting increased protein expression. Non-diabetic siRNA knockdown but not FZD7, RYK significantly decreased approximately 50% (*P 0.05) control siRNA. LECs, inhibited 40% FZD5 partially blocked could be restored Conclusions: seems mediate mainly through receptor tyrosine kinase like orphan 2 Frizzled-5 serving possible co-receptor smaller effect.

Language: Английский

Citations

1
Vangl-dependent mesenchymal thinning shapes the distal lung during murine sacculation DOI
Sarah V. Paramore, Carolina Trenado-Yuste, Rishabh Sharan

et al.

Developmental Cell, Journal Year: 2024, Volume and Issue: 59(10), P. 1302 - 1316.e5

Published: April 2, 2024

Language: Английский

Citations

9
Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling DOI Creative Commons
Samuel C. Griffiths, Jia Tan, Armin Wagner

et al.

eLife, Journal Year: 2024, Volume and Issue: 13

Published: May 23, 2024

The receptor tyrosine kinase ROR2 mediates noncanonical WNT5A signaling to orchestrate tissue morphogenetic processes, and dysfunction of the pathway causes Robinow syndrome, brachydactyly B, metastatic diseases. domain(s) mechanisms required for function, however, remain unclear. We solved crystal structure extracellular cysteine-rich (CRD) Kringle (Kr) domains found that, unlike other CRDs, CRD lacks signature hydrophobic pocket that binds lipids/lipid-modified proteins, such as WNTs, suggesting a novel mechanism ligand reception. Functionally, we showed CRD, but not domains, is minimally sufficient promote signaling, mutations in adjacent Kr impair secretion function. Moreover, using function-activating -perturbing antibodies against Frizzled (FZ) family WNT receptors, demonstrate involvement FZ WNT5A-ROR signaling. Thus, acts via its potentiate function super-complex includes transduce signals.

Language: Английский

Citations

6
Wnt-Ror-Dvl signalling and the dystrophin complex organize planar-polarized membrane compartments in C. elegans muscles DOI Creative Commons

Alice Peysson,

Noura Zariohi,

Marie Gendrel

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: June 10, 2024

Cell polarity mechanisms allow the formation of specialized membrane domains with unique protein compositions, signalling properties, and functional characteristics. By analyzing localization potassium channels proteins belonging to dystrophin-associated complex, we reveal existence distinct planar-polarized compartments at surface C. elegans muscle cells. We find that is controlled by a non-canonical Wnt cascade involving ligand EGL-20/Wnt, receptor CAM-1/Ror, intracellular effector DSH-1/Dishevelled. Interestingly, classical planar cell are not required for this process. Using time-resolved degradation, demonstrate -while it essentially in place end embryogenesis- dynamic state, requiring continued presence DSH-1 throughout post-embryonic life. Our results unsuspected complexity establish genetically tractable model system study cellular compartmentalization vivo.

Language: Английский

Citations

5
Wnt5a and Notum influence the temporal dynamics of cartilaginous mesenchymal condensations in developing trachea DOI Creative Commons
Natalia Bottasso-Arias, Megha Mohanakrishnan,

Sarah Trovillion

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2025, Volume and Issue: 13

Published: April 9, 2025

The trachea is essential for proper airflow to the lungs gas exchange. Frequent congenital tracheal malformations affect cartilage, causing collapse of central airway during respiratory cycle. We have shown that Notum, a Wnt ligand de-acylase attenuates canonical branch signaling pathway, necessary cartilaginous mesenchymal condensations. In Notum deficient tracheas, chondrogenesis delayed, and lumen narrowed. It unknown if non-canonical signaling. observed premature after deletion Wnt5a ligand. hypothesize are required mediate timely formation condensations, giving rise cartilage. Ex vivo culture tissue shows chemical inhibition pathway promotes earlier while presents delayed Furthermore, induction prevents On other hand, cell-cell interactions among chondroblasts increase in absence Wnt5a. By performing an unbiased analysis gene expression we detect by E11.5, mRNA genes extracellular matrix upregulated mutants. profile supports respectively. conclude cartilage patterning coordinating chondrogenesis. Thus, these studies shed light on molecular mechanisms underlying anomalies trachea.

Language: Английский

Citations

0
Inflammation and cancer cell survival: TRAF2 as a key player DOI Creative Commons
Adriana Albini, Luisa Di Paola, Giampiero Mei

et al.

Cell Death and Disease, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 14, 2025

Abstract TNF receptor-associated factor 2 (TRAF2) plays a crucial role in both physiological and pathological processes. It takes part the regulation of cell survival death, tissue regeneration, development, endoplasmic reticulum stress response, autophagy, homeostasis epithelial barrier adaptive innate immunity. Initially identified for its interaction with receptor (TNFR2), TRAF2 contains TRAF domain that enables homo- hetero-oligomerization, allowing it to interact multiple receptors signaling molecules. While best known mediating TNFR1 TNFR2 signaling, also modulates other pathways, including MAPK, NF-κB, Wnt/β-catenin cascades. By regulating NF-κB-inducing kinase (NIK), is key activator alternative NF-κB pathway, linking inflammatory diseases, immune dysfunction, tumorigenesis. In system, influences macrophage differentiation, activation, stimulates natural killer cytotoxicity. represses effector B- T-cell activity while sustaining regulatory function, thus promoting suppression. The lack fine-tuning leads excessive NF-kB driving chronic inflammation autoimmunity. Although can act as tumor suppressor, predominantly described promoter, expression has been correlated increased metastatic potential poorer prognosis several types cancer. Targeting or TRAF2-dependent pathways might represent promising anti-cancer therapeutic strategy.

Language: Английский

Citations

0
RNF43 and ZNRF3: Versatile regulators at the membrane and their role in cancer DOI Creative Commons
Shanshan Li, Jiahui Niu, Ron Smits

et al.

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2024, Volume and Issue: unknown, P. 189217 - 189217

Published: Nov. 1, 2024

Language: Английский

Citations

1
Wnt-Ror-Dvl signalling and the dystrophin complex organize planar-polarized membrane compartments inC. elegansmuscles DOI Creative Commons

Alice Peysson,

Noura Zariohi,

Marie Gendrel

et al.

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

Published: March 28, 2023

ABSTRACT Cell polarity mechanisms allow the formation of specialized membrane domains with unique protein compositions, signalling properties, and functional characteristics. By analysing localization potassium channels proteins belonging to dystrophin-associated complex, we reveal existence distinct planar-polarized compartments at surface C. elegans muscle cells. We find that is controlled by a non-canonical Wnt cascade involving ligand EGL-20/Wnt, receptor CAM-1/Ror, intracellular effector DSH-1/Dishevelled. Interestingly, classical planar cell are not required for this process. Using time-resolved degradation, demonstrate –while it essentially in place end embryogenesis– dynamic state, requiring continued presence DSH-1 throughout post-embryonic life. Our results unsuspected complexity establish novel genetically tractable model system study cellular compartmentalization vivo .

Language: Английский

Citations

1
Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling DOI Creative Commons
Samuel C. Griffiths, Jia Tan, Armin Wagner

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2021, Volume and Issue: unknown

Published: July 26, 2021

Abstract The receptor tyrosine kinase ROR2 mediates noncanonical WNT5A signaling to orchestrate tissue morphogenetic processes, and dysfunction of the pathway causes Robinow syndrome, Brachydactyly B metastatic diseases. domain(s) mechanisms required for function, however, remain unclear. We solved crystal structure extracellular cysteine-rich (CRD) Kringle (Kr) domains found that, unlike other CRDs, CRD lacks signature hydrophobic pocket that binds lipids/lipid-modified proteins, such as WNTs, suggesting a novel mechanism ligand reception. Functionally, we showed CRD, but not domains, is minimally sufficient promote signaling, mutations in adjacent Kr impair secretion function. Moreover, using function-activating -perturbing antibodies against Frizzled (FZ) family WNT receptors, demonstrate involvement FZ WNT5A-ROR signaling. Thus, acts via its potentiate function super-complex includes transduce signals.

Language: Английский

Citations

1