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Transcriptional regulation of cellular mechanosignaling by PREP1 (PKNOX1)

ABSTRACT: Mechanosignaling, initiated by the extracellular physical forces and propagated through the intracellular cytoskeletal network, triggers signaling cascades leading to processes such as embryogenesis, tissue maintenance and disease development. While signal transduction by transcription factors occurs downstream of cellular mechanosensing, nothing is known about the cell intrinsic mechanisms that can regulate mechanosignaling. Here we show that transcription factor PREP1 (PKNOX1) regulates the expression of LINC complex proteins and mechanotransduction of YAP-TAZ. PREP1 depletion upsets the nuclear membrane protein stoichiometry rendering nuclei soft. However, reduced nuclear tension is not conveyed to the cytoplasm, since these cells display fortified actomyosin network with bigger focal adhesion complexes resulting in greater traction forces at the substratum. Intriguingly, YAP-TAZ remains localized to the cytoplasm irrespective of the substrate rigidity indicating disrupted mechanotransduction. Our data demonstrate a hitherto unknown transcriptional mechanism which regulate mechanosignaling upstream of YAP-TAZ transduction.

ORGANISM(S): Homo sapiens

PROVIDER: GSE160286 | GEO | 2022/03/14

REPOSITORIES: GEO

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YAP regulates cell mechanics by controlling focal adhesion assembly

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2017-05-17 | E-MTAB-5217 | biostudies-arrayexpress

De-differentiation by Adenovirus E1A Due to Inactivation of Hippo Pathway Effectors YAP and TAZ [RNA-seq]

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2019-06-01 | GSE130136 | GEO

De-differentiation by Adenovirus E1A Due to Inactivation of Hippo Pathway Effectors YAP and TAZ [ChIP-seq]

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2017-04-19 | PXD003872 | Pride

Proteomic analysis glomeruli of PAN-treated rats

Project description:Podocytes are terminally differentiated cells at the kidney filtration barrier and exposed to considerable mechanical strain. Podocyte injury causes morphological changes as a result of cytoskeletal reorganizations and failure of the filtration barrier. The transcriptional co-activators YAP/TAZ are tightly controlled through hippo signaling and responsive to mechanical cues. Here, we show that YAP is upregulated upon podocyte injury to activate YAP-dependent target genes. This activation preceded the development of proteinuria. In contrast, similar perturbations of cells in culture did not reveal increased YAP activity but showed a downregulation of YAP/TAZ activity when cells were grown on stiff surface. However, culture of cells on soft matrix or inhibition of stress fiber formation allowed recapitulation of the damage-induced YAP upregulation indicating a mechanotransduction-dependent mechanism of YAP hyper-activity. Interestingly, increased expression of YAP targets was confirmed in renal biopsies from patients with glomerular disease. Consistently, pharmacological inhibition of YAP/TEAD activity ameliorated glomerular disease in vivo. These data suggest that perturbation of the mechanosensitive hippo signaling pathway may be a therapeutic principle in podocyte disease.

2017-05-02 | PXD003864 | Pride

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Project description:We report that loss of CCM3/PDCD10 in fibroblasts induces FAK/Src-paxillin signalling driving actomyosin-dependent mechanotransduction leading to YAP/TAZ signalling. In vivo, loss of CCM3 in fibroblasts drives excessive tissue remodelling leading to the dissemination of breast cancer cells to distant organs.

2021-05-06 | GSE155688 | GEO

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Project description:Fetal bone development occurs by endochondral conversion of avascular cartilage to vascularized bone at the growth plate. This requires coordinated mobilization of osteoblast precursors with blood vessels. In adult bone, vessel-adjacent osteoblast precursors are maintained by mechanical stimuli; however, the mechanisms by which these cells mobilize and respond to mechanical cues during embryonic development are unknown. Here, we unify osteoblast precursor co-mobilization and mechanotransduction in a single signaling pathway, via the mechanosensitive transcriptional regulators YAP and TAZ. We show that YAP and TAZ spatially couple osteoblast precursor mobilization to angiogenesis, regulate vascular loop morphogenesis to control growth plate remodeling, and mediate mechanoregulation of load-induced osteogenesis in embryonic bone. Mechanistically, YAP and TAZ uniquely regulate a subset of osteoblast-lineage cells, identified by single-cell RNA sequencing as vessel-associated osteoblast precursors. Among these cells, YAP and TAZ regulate expression of the angiogenic chemokine, Cxcl12. Functionally, in 3D human cell co-culture, CXCL12 treatment rescued angiogenesis impaired by stromal cell YAP/TAZ depletion. Together, these data establish new functions of the vessel-associated osteoblast precursors in endochondral bone development.

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