Suppression of anoikis in human intestinal epithelial cells: differentiation state-selective roles of α2β1, α3β1, α5β1, and α6β4 integrins

Beauséjour, Marco; Thibodeau, Sonya; Demers, Marie-Josée; Bouchard, Véronique; Gauthier, Rémy; Beaulieu, Jean‐François; Vachon, Pierre H.

doi:10.1186/1471-2121-14-53

Cited by 27 publications

(15 citation statements)

References 59 publications

(436 reference statements)

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“…laminins, collagens) and integrins (e.g. α2β1, α6β4) that can support cell adhesion and also signal to prevent anoikis [50][51][52]. However, since we did not specifically monitor the rate of apoptosis/anoikis levels, we cannot exclude that the depletion of these proteins had any impact on cell survival.…”

Section: Fibrillar Fn Promotes Spreading and A Contractile Phenotype mentioning

confidence: 99%

ILK supports RhoA/ROCK-mediated contractility of human intestinal epithelial crypt cells by inducing the fibrillogenesis of endogenous soluble fibronectin during the spreading process

Gagné

Benoit

Groulx

et al. 2020

BMC Mol and Cell Biol

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Background: Fibronectin (FN) assembly into an insoluble fibrillar matrix is a crucial step in many cell responses to extracellular matrix (ECM) properties, especially with regards to the integrin-related mechanosensitive signaling pathway. We have previously reported that the silencing of expression of integrin-linked kinase (ILK) in human intestinal epithelial crypt (HIEC) cells causes significant reductions in proliferation and spreading through concomitantly acquired impairment of soluble FN deposition. These defects in ILK-depleted cells are rescued by growth on exogenous FN. In the present study we investigated the contribution of ILK in the fibrillogenesis of FN and its relation to integrin-actin axis signaling and organization. Results: We show that de novo fibrillogenesis of endogenous soluble FN is ILK-dependent. This function seemingly induces the assembly of an ECM that supports increased cytoskeletal tension and the development of a fully spread contractile cell phenotype. We observed that HIEC cell adhesion to exogenous FN or collagen-I (Col-I) is sufficient to restore fibrillogenesis of endogenous FN in ILK-depleted cells. We also found that optimal engagement of the Ras homolog gene family member A (RhoA) GTPase/Rho-associated kinase (ROCK-1, ROCK-2)/myosin light chain (MLC) pathway, actin ventral stress fiber formation, and integrin adhesion complex (IAC) maturation rely primarily upon the cell's capacity to execute FN fibrillogenesis, independent of any significant ILK input. Lastly, we confirm the integrin α5β1 as the main integrin responsible for FN assembly, although in ILK-depleted cells αV-class integrins expression is needed to allow the rescue of FN fibrillogenesis on exogenous substrate. Conclusion: Our study demonstrates that ILK specifically induces the initiation of FN fibrillogenesis during cell spreading, which promotes RhoA/ROCK-dependent cell contractility and maturation of the integrin-actin axis structures. However, the fibrillogenesis process and its downstream effect on RhoA signaling, cell contractility and spreading are ILK-independent in human intestinal epithelial crypt cells.

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Section: Fibrillar Fn Promotes Spreading and A Contractile Phenotype mentioning

confidence: 99%

ILK supports RhoA/ROCK-mediated contractility of human intestinal epithelial crypt cells by inducing the fibrillogenesis of endogenous soluble fibronectin during the spreading process

Gagné

Benoit

Groulx

et al. 2020

BMC Mol and Cell Biol

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“…When cells are not adhered to the proper extracellular matrices, they will undergo a specialized form of apoptosis known as anoikis. Notably, when caspases are activated, the β4 cytoplasmic tail is cleaved leading to apoptosis (25, 26). …”

Section: Structure and Normal Function Of Integrin α6β4mentioning

confidence: 99%

Clinical significance of the integrin α6β4 in human malignancies

Stewart

O’Connor

2015

Laboratory Investigation

182

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Integrin α6β4 is a cellular adhesion molecule that binds to laminins in the extracellular matrix and nucleates the formation of hemidesmosomes. During carcinoma progression, integrin α6β4 is released from hemidesmosomes, where it can then signal to facilitate multiple aspects of tumor progression including sustaining proliferative signaling, tumor invasion and metastasis, evasion of apoptosis, and stimulation of angiogenesis. The integrin achieves these ends by cooperating with growth factor receptors including EGFR, ErbB-2, and c-Met to amplify downstream pathways such as PI3K, AKT, MAPK and the Rho family small GTPases. Furthermore, it dramatically alters the transcriptome toward a more invasive phenotype by controlling promoter DNA demethylation of invasion and metastasis-associated proteins, such as S100A4 and autotaxin, and upregulates and activates key tumor promoting transcription factors such as the NFATs and NFkB. Expression of integrin α6β4 has been studied in many human malignancies where its overexpression is associated with aggressive behavior and a poor prognosis. This review provides an assessment of integrin α6β4 expression patterns and their prognostic significance in human malignancies, and describes key signaling functions of integrin α6β4 that contribute to tumor progression.

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“…). Interestingly, IECs show differential apoptosis sensitivity depending on their degree of differentiation . The luminal surface of the epithelium and the crypt region are the more susceptible sites to undergo apoptosis.…”

Section: Detachment‐induced Apoptosis In Iecsmentioning

confidence: 99%