High-Molecular-Weight Hyaluronan Is a Hippo Pathway Ligand Directing Cell Density-Dependent Growth Inhibition via PAR1b

Ooki, Takuya; Murata‐Kamiya, Naoko; Takahashi-Kanemitsu, Atsushi; Wu, Weida; Hatakeyama, Masanori

doi:10.1016/j.devcel.2019.04.018

Cited by 76 publications

(67 citation statements)

References 38 publications

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“…Loss of this normal HMWHA coating stimulates cell proliferation. Growth suppressive mechanisms of HMWHA are known to involve density-dependent Hippo pathway signaling as well as engagement of early contact inhibition through Ezrin-Radixin-Moesin (ERM) actin-binding proteins 49,50 . The buildup of perivascular HA in wildtype mice during hypoxia therefore serves to block medial proliferation.…”

Section: Discussionmentioning

confidence: 99%

Extracellular Superoxide Dismutase Regulates Early Vascular Hyaluronan Remodeling in Hypoxic Pulmonary Hypertension

Tseng

Allawzi

et al. 2020

Sci Rep

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chronic hypoxia leads to pathologic remodeling of the pulmonary vasculature and pulmonary hypertension (PH). The antioxidant enzyme extracellular superoxide dismutase (SOD3) protects against hypoxia-induced pH. Hyaluronan (HA), a ubiquitous glycosaminoglycan of the lung extracellular matrix, is rapidly recycled at sites of vessel injury and repair. We investigated the hypothesis that SOD3 preserves HA homeostasis by inhibiting oxidative and enzymatic hyaluronidase-mediated HA breakdown. In SOD3-deficient mice, hypoxia increased lung hyaluronidase expression and activity, hyaluronan fragmentation, and effacement of HA from the vessel wall of small pulmonary arteries. Hyaluronan fragmentation corresponded to hypoxic induction of the cell surface hyaluronidase-2 (Hyal2), which was localized in the vascular media. Human pulmonary artery smooth muscle cells (HPASMCs) demonstrated hypoxic induction of Hyal2 and SOD-suppressible hyaluronidase activity, congruent to our observations in vivo. fragmentation of homeostatic high molecular weight HA promoted HpASMc proliferation in vitro, whereas pharmacologic inhibition of hyaluronidase activity prevented hypoxia-and oxidant-induced proliferation. Hypoxia initiates SOD3-dependent alterations in the structure and regulation of hyaluronan in the pulmonary vascular extracellular matrix. these changes occurred soon after hypoxia exposure, prior to appearance of pH, and may contribute to the early pathogenesis of this disease.Pulmonary hypertension (PH) is an incurable and fatal disease characterized by intimal thickening, muscular hypertrophy, excessive matrix deposition, and stiffening of arteries in the lung. Chronic hypoxia is a major cause and consequence of PH in humans. It is the most prevalent etiology of precapillary PH in humans (WHO Group 3 disease). The onset of PH in patients with hypoxia due to intrinsic lung disease portends a grim prognosis for survival, post-transplant outcome, and quality of life 1,2 . Therefore, there is an urgent need for research on the molecular pathogenesis of hypoxic pulmonary hypertension.One facet of this disease is the presence of high oxidative stress within the vessel wall and perivascular matrix 3 . Extracellular superoxide dismutase (SOD3) is crucial for neutralization of this stress. Global knockout 4 , selective deletion from smooth muscle cells 5 , and disrupted matrix-binding single nucleotide polymorphisms 6 of SOD3 result in a great susceptibility to hypoxia-induced vascular inflammation, fibrosis, and PH. On the other hand, lung-specific overexpression of SOD3 7 , adenoviral gene transfer of human SOD3 8 , and treatment with an inorganic metalloporphyrin SOD3 mimetic 9 are protective against PH in rodent models. In the advanced stages of PH in humans, SOD3 levels are epigenetically reduced by histone deacetylation 10 .There is a critical gap in our understanding of how the extracellular oxidative environment can lead to irreversible pulmonary vascular remodeling in chronic hypoxia. Amassing evidence points to a central role f...

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Section: Discussionmentioning

confidence: 99%

Extracellular Superoxide Dismutase Regulates Early Vascular Hyaluronan Remodeling in Hypoxic Pulmonary Hypertension

Tseng

Allawzi

et al. 2020

Sci Rep

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“…Moreover, it has recently been reported that MST1/2 (mammalian Ste20-like kinase 1/2), a component of the tumor-suppressing Hippo signaling pathway, is a novel substrate of PAR1b. 111 Therefore, further investigation may reveal the involvement of perturbed MST1/2-LATS1/2-YAP/TAZ signaling induced by the CagA-PAR1b complex in the pathobiological action of the CagA protein.…”

Section: Molecular Structure Of the Caga Proteinmentioning

confidence: 99%

Molecular anatomy and pathogenic actions of Helicobacter pylori CagA that underpin gastric carcinogenesis

2019

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Chronic infection with Helicobacter pylori cagA-positive strains is the strongest risk factor for gastric cancer. The cagA gene product, CagA, is delivered into gastric epithelial cells via the bacterial type IV secretion system. Delivered CagA then undergoes tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs in its C-terminal region and acts as an oncogenic scaffold protein that physically interacts with multiple host signaling proteins in both tyrosine phosphorylation-dependent and-independent manners. Analysis of CagA using in vitro cultured gastric epithelial cells has indicated that the nonphysiological scaffolding actions of CagA cell-autonomously promote the malignant transformation of the cells by endowing the cells with multiple phenotypic cancer hallmarks: sustained proliferation, evasion of growth suppressors, invasiveness, resistance to cell death, and genomic instability. Transgenic expression of CagA in mice leads to in vivo oncogenic action of CagA without any overt inflammation. The in vivo oncogenic activity of CagA is further potentiated in the presence of chronic inflammation. Since Helicobacter pylori infection triggers a proinflammatory response in host cells, a feedforward stimulation loop that augments the oncogenic actions of CagA and inflammation is created in CagA-injected gastric mucosa. Given that Helicobacter pylori is no longer colonized in established gastric cancer lesions, the multistep nature of gastric cancer development should include a "hit-and-run" process of CagA action. Thus, acquisition of genetic and epigenetic alterations that compensate for CagA-directed cancer hallmarks may be required for completion of the "hit-and-run" process of gastric carcinogenesis.

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“…1). For instance, the Hippo pathway is regulated by cell-cell contact 14,15) and cell polarity, [16][17][18] as well as by mechanical cues [19][20][21][22][23] such as extracellular matrix stiffness and traction forces exerted by neighboring cells. In addition to those physical cues, a general role of extracellular signaling pathways has become apparent, such as G-proteincoupled receptors [24][25][26][27] and the Wnt signaling pathway, [28][29][30][31] in the regulation of the Hippo pathway.…”

Section: Introductionmentioning

confidence: 99%

The Emerging Link between the Hippo Pathway and Non-coding RNA

Shimoda

Moroishi

2020

Biological & Pharmaceutical Bulletin

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The Hippo intracellular signaling pathway plays a pivotal role in cell fate determination. Although previous studies have identified many components of the Hippo pathway, the whole picture of the Hippo network is just beginning to be delineated. Recent discoveries in the past decade have shed light on a newly discovered signaling network where the Hippo pathway interplays with several types of non-coding RNAs, including microRNAs, long non-coding RNAs and circular RNAs, to mediate diverse biological processes. Those non-coding RNAs communicate with each other to maintain cellular homeostasis. In this review article, we summarize the current and emerging understanding of the roles of non-coding RNAs in the regulation of and by the Hippo pathway.

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High-Molecular-Weight Hyaluronan Is a Hippo Pathway Ligand Directing Cell Density-Dependent Growth Inhibition via PAR1b

Cited by 76 publications

References 38 publications

Extracellular Superoxide Dismutase Regulates Early Vascular Hyaluronan Remodeling in Hypoxic Pulmonary Hypertension

Extracellular Superoxide Dismutase Regulates Early Vascular Hyaluronan Remodeling in Hypoxic Pulmonary Hypertension

Molecular anatomy and pathogenic actions of Helicobacter pylori CagA that underpin gastric carcinogenesis

The Emerging Link between the Hippo Pathway and Non-coding RNA

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