THY1-mediated mechanisms converge to drive YAP activation in skin homeostasis and repair

Sedov, Egor; Koren, Elle; Chopra, Sucheta; Ankawa, Roi; Yosefzon, Yahav; Yusupova, Marianna; Weiss, Lucien E.; Mahly, Adnan; Soffer, Arad; Feldman, Alona; Luxenburg, Chen; Shechtman, Yoav; Fuchs, Yaron

doi:10.1038/s41556-022-00944-6

Cited by 17 publications

(10 citation statements)

References 87 publications

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“…For example, Barker and Hagood suggested that THY1 can participate in the trafficking and partitioning of signaling molecules at the lipid rafts and may act alternately to sequester or traffic signaling molecules, resulting in either inhibition or activation of downstream signaling, such as SFKs, in different cell contexts [ 46 ]. Indeed, our results clearly showed that SRC activity was inhibited by THY1 in NPC, which is in accordance with the inhibitory role of THY1 in SRC activity in fibroblasts [ 10 ], basal cells [ 35 ], and neuron cells [ 47 ]. Other studies reported that the presence of THY1 is essential for activation of SRC by thrombospondin/hep I [ 48 , 49 ].…”

Section: Discussionsupporting

confidence: 88%

“…A recent study has shown that THY1 expressed on mouse basal cells can interact with integrin β1 to suppress its downstream activation of SRC, and loss of THY1 expression is associated with activation of SRC, dissociation of adherens junctions, and enhanced epidermal wound repair [ 35 ]. That study suggested that THY1 can play a role in cell adhesion/migration via modulation of SRC activity in the skin, which is in agreement with our current finding.…”

Section: Discussionmentioning

confidence: 99%

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THY1 (CD90) Maintains the Adherens Junctions in Nasopharyngeal Carcinoma via Inhibition of SRC Activation

Chen

Chau

Yuen

et al. 2023

Cancers

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We had previously shown that THY1 (CD90) is a tumor suppressor in nasopharyngeal carcinoma (NPC) and that its down-regulation and loss of expression are associated with tumor metastasis, yet the mechanism leading to such effects remains unknown. In this study we show that tumor invasion could be suppressed by THY1 via adherens junction formation in a few NPC cell lines, and knockdown of THY1 would disrupt this cell-cell adhesion phenotype. Mechanistically, the activity of the SRC family kinase (SFK) member, SRC, and canonical Wnt signaling were dramatically reduced when THY1 was constitutively expressed. Previous studies by others have found that high levels of SRC activity in NPCs are associated with EMT and a poor prognosis. We hypothesized that THY1 can suppress tumor invasion in NPC via inhibition of SRC. By gene silencing of SRC, we found that the in vitro NPC cell invasion was significantly reduced and adherens junctions were restored. Through proteomic analysis, we identified that platelet-derived growth factor receptor β (PDGF-Rβ) and protein tyrosine phosphatase nonreceptor type 22 (PTPN22) are novel and potential binding partners of THY1, which were subsequently verified by co-immunoprecipitation (co-IP) analysis. The ligand of PDGF-Rβ (PDGF-BB) could highly induce SRC activation and NPC cell invasion, which could be almost completely suppressed by THY1 expression. On the other hand, the PTPN22 siRNA could enhance both the SRC activities and the cell invasion and could also disrupt the adherens junctions in the THY1-expressing NPC cells; the original THY1-induced phenotypes were reverted when the PTPN22 expression was reduced. Together, our results identified that PTPN22 is essential for THY1 to suppress cell invasion and SRC activity, maintain tight adherens junctions, and prevent NPC metastasis. These results suggested that PDGF-Rβ and SRC can be used as drug targets for suppressing NPC metastasis. Indeed, our in vivo assay using the SRC inhibitor KX2-391, clearly showed that inhibition of SRC signaling can prevent the metastasis of NPC, indicating that targeting SRC can be a promising approach to control the NPC progression.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

THY1 (CD90) Maintains the Adherens Junctions in Nasopharyngeal Carcinoma via Inhibition of SRC Activation

Chen

Chau

Yuen

et al. 2023

Cancers

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“…During the preparation of this manuscript, a paper stating that Thy-1 absence promotes, rather than delays wound healing, was published by Sedov et al in Nat Cell Biol [ 34 ]. These authors reported that the wound healing process and hair follicle regeneration were accelerated in mice lacking Thy-1 ( Thy-1 −/− ) due to proliferation dependent on YAP signaling.…”

Section: Discussionmentioning

confidence: 99%

The GPI-Anchored Protein Thy-1/CD90 Promotes Wound Healing upon Injury to the Skin by Enhancing Skin Perfusion

Pérez

León

López

et al. 2022

IJMS

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Wound healing is a highly regulated multi-step process that involves a plethora of signals. Blood perfusion is crucial in wound healing and abnormalities in the formation of new blood vessels define the outcome of the wound healing process. Thy-1 has been implicated in angiogenesis and silencing of the Thy-1 gene retards the wound healing process. However, the role of Thy-1 in blood perfusion during wound closure remains unclear. We proposed that Thy-1 regulates vascular perfusion, affecting the healing rate in mouse skin. We analyzed the time of recovery, blood perfusion using Laser Speckle Contrast Imaging, and tissue morphology from images acquired with a Nanozoomer tissue scanner. The latter was assessed in a tissue sample taken with a biopsy punch on several days during the wound healing process. Results obtained with the Thy-1 knockout (Thy-1−/−) mice were compared with control mice. Thy-1−/− mice showed at day seven, a delayed re-epithelialization, increased micro- to macro-circulation ratio, and lower blood perfusion in the wound area. In addition, skin morphology displayed a flatter epidermis, fewer ridges, and almost no stratum granulosum or corneum, while the dermis was thicker, showing more fibroblasts and fewer lymphocytes. Our results suggest a critical role for Thy-1 in wound healing, particularly in vascular dynamics.

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“…Yes-associated protein 1 (YAP/YAP1) is a transcriptional regulator in the Hippo signaling pathway interacting with GPI-APs. [27] It has been shown that THY1, a basal epidermis GPI-AP, could inhibit YAP in a Src-kinase dependent manner to regulate cell-matrix and cell-cell interaction [28] and YAP deregulates GPI-AP expression or its interaction with other signaling partners within the lipid rafts via regulating the Hippo signaling pathway. [29] YAP-regulated GPI-AP arrangement and localization occur via the mechanocytoskeleton signaling mechanism, which may be linked to GPI-AP-mediated actin cytoskeleton remodeling, [30] and thus modulate other cellular mechanisms.…”

Section: Uniprot Idsmentioning

confidence: 99%

Investigation of Glycosylphosphatidylinositol (GPI)‐Plasma Membrane Interaction in Live Cells and the Influence of GPI Glycan Structure on the Interaction

Kundu,

Jaiswal,

Babu Mullapudi

et al. 2023

Chemistry A European J

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Glycosylphosphatidylinositols (GPIs) need to interact with other components in the cell membrane to transduce transmembrane signals. A bifunctional GPI probe was employed for photoaffinity‐based proximity labelling and identification of GPI‐interacting proteins in the cell membrane. This probe contained the entire core structure of GPIs and was functionalized with photoreactive diazirine and clickable alkyne to facilitate its crosslinking with proteins and attachment of an affinity tag. It was disclosed that this probe was more selective than our previously reported probe containing only a part structure of the GPI core for cell membrane incorporation and an improved probe for studying GPI‐cell membrane interaction. Eighty‐eight unique membrane proteins, many of which are related to GPIs/GPI‐anchored proteins, were identified utilizing this probe. The proteomics dataset is a valuable resource for further analyses and data mining to find new GPI‐related proteins and signalling pathways. A comparison of these results with those of our previous probe provided direct evidence for the profound impact of GPI glycan structure on its interaction with the cell membrane.

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THY1-mediated mechanisms converge to drive YAP activation in skin homeostasis and repair

Cited by 17 publications

References 87 publications

THY1 (CD90) Maintains the Adherens Junctions in Nasopharyngeal Carcinoma via Inhibition of SRC Activation

THY1 (CD90) Maintains the Adherens Junctions in Nasopharyngeal Carcinoma via Inhibition of SRC Activation

The GPI-Anchored Protein Thy-1/CD90 Promotes Wound Healing upon Injury to the Skin by Enhancing Skin Perfusion

Investigation of Glycosylphosphatidylinositol (GPI)‐Plasma Membrane Interaction in Live Cells and the Influence of GPI Glycan Structure on the Interaction

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