Src family kinases inhibit differentiation of intestinal epithelial cells through the Hippo effector YAP1

Fallah, Sepideh; Beaulieu, Jean‐François

doi:10.1242/bio.058904

Cited by 7 publications

(9 citation statements)

References 73 publications

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“…In contrast, McNeill et al 174 discovered that YAP/TAZ activation by Lats1/2 deletion could promote the differentiation of nephron progenitor cells into interstitial myofibroblastic cells in the kidney. In addition to the aforementioned cells, the Hippo pathway has also been reported to regulate specific cell differentiation in other tissues or organs, such as skin keratinocytes, 154 intestinal epithelial cells, 175 hepatocytes and biliary cells. 176,177 Overall, these findings suggest that Hippo pathway components, especially YAP/TAZ, are involved in cell growth/proliferation and differentiation in different tissues or organs under diverse contexts.…”

Section: Critical Physiological Functions Of the Hippo Pathwaymentioning

confidence: 99%

The Hippo signalling pathway and its implications in human health and diseases

Lan

et al. 2022

Sig Transduct Target Ther

225

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As an evolutionarily conserved signalling network, the Hippo pathway plays a crucial role in the regulation of numerous biological processes. Thus, substantial efforts have been made to understand the upstream signals that influence the activity of the Hippo pathway, as well as its physiological functions, such as cell proliferation and differentiation, organ growth, embryogenesis, and tissue regeneration/wound healing. However, dysregulation of the Hippo pathway can cause a variety of diseases, including cancer, eye diseases, cardiac diseases, pulmonary diseases, renal diseases, hepatic diseases, and immune dysfunction. Therefore, therapeutic strategies that target dysregulated Hippo components might be promising approaches for the treatment of a wide spectrum of diseases. Here, we review the key components and upstream signals of the Hippo pathway, as well as the critical physiological functions controlled by the Hippo pathway. Additionally, diseases associated with alterations in the Hippo pathway and potential therapies targeting Hippo components will be discussed.

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Section: Critical Physiological Functions Of the Hippo Pathwaymentioning

confidence: 99%

The Hippo signalling pathway and its implications in human health and diseases

Lan

et al. 2022

Sig Transduct Target Ther

225

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“…For instance, YAP1 has F I G U R E 3 Regulation of intestinal epithelial cell differentiation by Src family kinases acts through YAP1. The promoting effect of Src family kinase inhibition on the differentiation of absorptive and goblet cells was accompanied by an increase in YAP1 phosphorylation, cytoplasmic sequestration and degradation, which released its repression on the expression of prodifferentiation transcription factors such as CDX2 and HNF4α P1 (Fallah & Beaulieu, 2021). Figure adapted from Fallah (2021) been shown to repress HNF-4α expression in the liver that is accompanied by repression of hepatocyte differentiation and induction of biliary epithelial cell and fibroblast proliferation (Fitamant et al, 2015;Lee et al, 2016).…”

Section: Yap1 and Taz In Intestinal Epithelial Cellsmentioning

confidence: 99%

“…The repressive activity on intestinal differentiation mediated by YAP1 but not TAZ is more puzzling. Based on shRNA-driven experiments, YAP1 appears to exert its effects by repressing the expression of tissue-specific transcription factors such as CDX2 or affecting their stability as observed for the HNF-4α P1 form, which in turn regulates the expression of intestinal cell markers (Fallah & Beaulieu, 2021). No such effects were observed in TAZ knockdown cells.…”

Section: Yap1 and Taz In Intestinal Epithelial Cellsmentioning

confidence: 99%

“…In this second strategy, we tested the hypothesis that the prodifferentiation effects observed in intestinal cells in response to SFKs inhibitor treatments may be the result of YAP1/TAZ inactivation. HT29 and Caco‐2/15 cells were treated with the two well‐documented SFK inhibitors (SFKi), dasatinib and pyrazolopyrimidine (PP2), to study the effects on YAP1 and TAZ and on intestinal differentiation (Fallah & Beaulieu, 2021). As expected from previous studies, treatments with SFKi led to a sharp reduction of YAP1 expression and loss of nuclear localization consistent with an increase of YAP1 serine 127 phosphorylation in both cell types, which were accompanied by a stimulation of the expression of intestinal prodifferentiation transcription factors and differentiation markers (Figure 3).…”

Section: Yap1 and Taz In Intestinal Epithelial Cellsmentioning

confidence: 99%

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Differential influence of YAP1 and TAZ on differentiation of intestinal epithelial cell: A review

Fallah

Beaulieu

2022

The Anatomical Record

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Intestinal cell stemness, proliferation and differentiation are complex processes all occurring in distinct compartments of the crypt that need to be closely regulated to ensure proper epithelial renewal. The involvement of the Hippo pathway in intestinal epithelial proliferation and regeneration after injury via the regulation of its effectors YAP1 and TAZ has been well-documented over the last decade. The implication of YAP1 and TAZ on intestinal epithelial cell differentiation is less clear. Using intestinal cell models in which the expression of YAP1 and TAZ can be modulated, our group showed that YAP1 inhibits differentiation of the two main intestinal epithelial cell types, goblet and absorptive cells through a specific mechanism involving the repression of prodifferentiation transcription factor CDX2 expression. Further analysis provided evidence that the repressive effect of YAP1 on intestinal differentiation is mediated by regulation of the Hippo pathway by Src family kinase activity. Interestingly, the TAZ paralog does not seem to be involved in this process, which provides another example of the lack of perfect complementarity of the two main Hippo effectors.

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“…The human colon carcinoma cell line Caco-2/15 (27), a stable clone of the parental Caco-2 cell line [HBT37; American Type Culture Collection (ATCC), Rockville, MD], fully characterized elsewhere (28,29), was grown under culture procedures detailed previously (30). The Caco-2/15 cell line was used for its ability to spontaneously initiate a differentiation program as an experimental cell model for villus epithelial cells (27)(28)(29)31).…”

Section: Cell Culturementioning

confidence: 99%

Fibrin(ogen) Is Constitutively Expressed by Differentiated Intestinal Epithelial Cells and Mediates Wound Healing

et al. 2022

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Fibrinogen is a large molecule synthesized in the liver and released in the blood. Circulating levels of fibrinogen are upregulated after bleeding or clotting events and support wound healing. In the context of an injury, thrombin activation drives conversion of fibrinogen to fibrin. Fibrin deposition contains tissue damage, stops blood loss, and prevents microbial infection. In most circumstances, fibrin needs to be removed to allow the resolution of inflammation and tissue repair, whereas failure of this may lead to the development of various disorders. However, the contribution of fibrinogen to tissue inflammation and repair is likely to be context-dependent. In this study, the concept that fibrin needs to be removed to allow tissue repair and to reduce inflammation is challenged by our observations that, in the intestine, fibrinogen is constitutively produced by a subset of intestinal epithelial cells and deposited at the basement membrane as fibrin where it serves as a substrate for wound healing under physiological conditions such as epithelial shedding at the tip of the small intestinal villus and surface epithelium of the colon as well as under pathological conditions that require rapid epithelial repair. The functional integrity of the intestine is ensured by the constant renewal of its simple epithelium. Superficial denuding of the epithelial cell layer occurs regularly and is rapidly corrected by a process called restitution that can be influenced by various soluble and insoluble factors. Epithelial cell interaction with the extracellular matrix greatly influences the healing process by acting on cell morphology, adhesion, and migration. The functional contribution of a fibrin(ogen) matrix in the intestine was studied under physiological and pathological contexts. Our results (immunofluorescence, immunoelectron microscopy, and quantitative PCR) show that fibrin(ogen) is a novel component of the basement membrane associated with the differentiated epithelial cell population in both the small intestine and colon. Fibrin(ogen) alone is a weak ligand for epithelial cells and behaves as an anti-adhesive molecule in the presence of type I collagen. Furthermore, the presence of fibrin(ogen) significantly shortens the time required to achieve closure of wounded epithelial cell monolayers and co-cultures in a PI3K-dependent manner. In human specimens with Crohn’s disease, we observed a major accumulation of fibrin(ogen) throughout the tissue and at denuded sites. In mice in which fibrin formation was inhibited with dabigatran treatment, dextran sulfate sodium administration provoked a significant increase in the disease activity index and pathological features such as mucosal ulceration and crypt abscess formation. Taken together, these results suggest that fibrin(ogen) contributes to epithelial healing under both normal and pathological conditions.

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Src family kinases inhibit differentiation of intestinal epithelial cells through the Hippo effector YAP1

Cited by 7 publications

References 73 publications

The Hippo signalling pathway and its implications in human health and diseases

The Hippo signalling pathway and its implications in human health and diseases

Differential influence of YAP1 and TAZ on differentiation of intestinal epithelial cell: A review

Fibrin(ogen) Is Constitutively Expressed by Differentiated Intestinal Epithelial Cells and Mediates Wound Healing

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