α8β1 integrin regulates nutrient absorption through an Mfge8-PTEN dependent mechanism

Khalifeh-Soltani, Amin; Ha, Arnold; Podolsky, Michael J.; McCarthy, Donald A; McKleroy, William; Azary, Saeedeh; Sakuma, Stephen; Tharp, Kevin M.; Wu, Nanyan; Yokosaki, Yasuyuki; Hart, Daniel; Stahl, Andreas; Atabai, Kamran

doi:10.7554/elife.13063

Cited by 29 publications

(38 citation statements)

References 48 publications

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“…In vascular smooth muscle cells (31,32) and intestinal epithelial cells, knockdown of a8 leads to less active RhoA. In contrast to this scenario, a8b1 ligation in gastric smooth muscle prevents RhoA activation (6). Similar to gastric smooth muscle, we found that a8b1 ligation in ASM prevents RhoA activation and contraction.…”

Section: Discussionmentioning

confidence: 51%

“…Mice with smooth muscle-specific deletion of a8b1 integrin have enhanced force of tracheal smooth muscle contraction in response to IL-13, and Mfge8 binding to a8b1 integrin is essential to abrogate the enhanced contraction. Previous studies have identified the role of a8 in vascular and gastric smooth muscle as well as in intestinal epithelial cells (6,13,31). However, the role of a8b1 in RhoA regulation differs among these cell types.…”

Section: Discussionmentioning

confidence: 99%

“…Smooth muscle dissected from mouse posterior tracheas were used for quantification of PTEN activity by using a PTEN activity ELISA kit (Echelon, San Jose, CA, USA) as previously described (6). Briefly, PTEN activity ELISA kit quantifies the phosphatase activity of PTEN by detection of the product phosphatidylinositol 4,5-bisphosphate.…”

Section: Pten Activity Assaymentioning

confidence: 99%

“…avb3 and avb5 integrins are the canonical receptors for Mfge8 (11,12). In addition to these 2 receptors, we found that the RGD-binding integrin a8b1, which is highly expressed in smooth muscle cells (13)(14)(15), is also a receptor for Mfge8 and regulates the force of gastric antral smooth muscle contraction (6). We first examined if any of these integrin receptors (avb3, avb5, and a8b1) were involved in mediating the effects of Mfge8 on ASM contraction.…”

Section: Mfge8 Ligation Of the A8b1 Integrin Prevents The Effect Of Imentioning

confidence: 99%

“…The present study investigated the molecular mechanisms involved in Mfge8 regulation of RhoA in ASM contraction. Based on our recent report on the role of RGD-binding integrin a8b1 in promoting nutrient absorption through regulation of antral smooth muscle contractile force (6), we hypothesized that an a8b1-PTEN pathway might be involved in mediating the effect of Mfge8 on ASM contraction in the setting of allergic inflammation. Toward this end, we observed that Mfge8 ligation of a8b1 integrin modulates cytokine-mediated airway contraction in ASM by modulating the PI3K pathway.…”

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confidence: 99%

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The Mfge8‐α8β1;1‐PTEN pathway regulates airway smooth muscle contraction in allergic inflammation

Khalifeh-Soltani

et al. 2018

FASEB j.

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Asthma affects ∼300 million people worldwide. Despite multiple treatment options, asthma treatment remains unsatisfactory in a subset of patients. Airway obstruction is a hallmark of allergic asthma and is largely due to airway smooth muscle hypercontractility induced by airway inflammation. Identification of molecular pathways that regulate airway smooth muscle hypercontractility is of considerable therapeutic interest. We previously identified roles for milk fat globule epidermal growth factor-like 8 (Mfge8) in opposing the effects of allergic inflammation on increasing airway smooth muscle contractile force. In this study, we delineate the signaling pathway by which Mfge8 mediates these effects. By using genetic and pharmacologic approaches, we show that the α8β1 integrin and the phosphatase and tensin homolog (PTEN) mediate the effects of Mfge8 on preventing IL-13-induced increases in airway contractility. Tracheal rings from mice with smooth muscle-specific deletion of α8β1 or PTEN have enhanced contraction in response to treatment with IL-13. Enhanced IL-13-induced tracheal ring contraction in Mfge8 mice was abolished by treatment with the PI3K inhibitor. Mechanistically, IL-13 induces ubiquitination and degradation of PTEN protein. Our findings identify a role for the Mfge8-α8β1-PTEN pathway in regulating the force of airway smooth muscle contraction in the setting of allergic inflammation.-Khalifeh-Soltani, A., Gupta, D., Ha, A., Podolsky, M. J., Datta, R., Atabai, K. The Mfge8-α8β1-PTEN pathway regulates airway smooth muscle contraction in allergic inflammation.

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Section: Discussionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Section: Pten Activity Assaymentioning

confidence: 99%

Section: Mfge8 Ligation Of the A8b1 Integrin Prevents The Effect Of Imentioning

confidence: 99%

mentioning

confidence: 99%

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The Mfge8‐α8β1;1‐PTEN pathway regulates airway smooth muscle contraction in allergic inflammation

Khalifeh-Soltani

et al. 2018

FASEB j.

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Induced hepatic stellate cell integrin, α8β1, enhances cellular contractility and TGFβ activity in liver fibrosis

Nishimichi

Tsujino

Kanno

et al. 2021

The Journal of Pathology

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No effective therapy exists for fatal fibrosis. New therapeutic targets are needed for hepatic fibrosis because the incidence keeps increasing. The activation and differentiation of fibroblasts into myofibroblasts that causes excessive matrix deposition is central to fibrosis. Here, we investigated whether (and which) integrin receptors for matrix proteins activate hepatic stellate cells (HSCs). First, integrin α‐subunits were investigated systematically for their expression over the course of HSC activation and their distribution on fibroblasts and other systemic primary cells. The most upregulated in plate culture‐activated HSCs and specifically expressed across fibroblast linages was the α8 subunit. An anti‐α8 neutralizing mAb was evaluated in three different murine fibrosis models: for cytotoxic (CCl4 treatment), non‐alcoholic steatohepatitis‐associated and cholestatic fibrosis. In all models, pathology and fibrosis markers (hydroxyproline and α‐smooth muscle actin) were improved following the mAb injection. We also CCl4‐treated mice with inducible Itga8−/−; these mice were protected from increased hydroxyproline levels. Furthermore, ITGA8 was upregulated in specimens from 90 patients with liver fibrosis, indicating the relevance of our findings to liver fibrosis in people. Mechanistically, inhibition or ligand engagement of HSC α8 suppressed and enhanced myofibroblast differentiation, respectively, and HSC/fibroblast α8 activated latent TGFβ. Finally, integrin α8β1 potentially fulfils the growing need for anti‐fibrotic drugs and is an integrin not to be ignored. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

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Integrin α8 and Its Ligand Nephronectin in Health and Disease

Wilson

Hung

Schnapp

2023

Biology of Extracellular Matrix

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α8β1 integrin regulates nutrient absorption through an Mfge8-PTEN dependent mechanism

Cited by 29 publications

References 48 publications

The Mfge8‐α8β1;1‐PTEN pathway regulates airway smooth muscle contraction in allergic inflammation

The Mfge8‐α8β1;1‐PTEN pathway regulates airway smooth muscle contraction in allergic inflammation

Induced hepatic stellate cell integrin, α8β1, enhances cellular contractility and TGFβ activity in liver fibrosis

Integrin α8 and Its Ligand Nephronectin in Health and Disease

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