Tsc1 regulates tight junction independent of mTORC1

Tuberous sclerosis complex 1 (Tsc1) is a tumor suppressor that functions together with Tsc2 to negatively regulate the mechanistic target of rapamycin complex 1 (mTORC1) activity. Here, we show that Tsc1 has a critical role in the tight junction (TJ) formation of epithelium, independent of its role in Tsc2 and mTORC1 regulation. When an epithelial cell establishes contact with neighboring cells, Tsc1, but not Tsc2, migrates from the cytoplasm to junctional membranes, in which it binds myosin 6 to anchor the perijunctional actin cytoskeleton to β-catenin and ZO-1. In its absence, perijunctional actin cytoskeleton fails to form. In mice, intestine-specific or inducible, whole-body Tsc1 ablation disrupts adherens junction/TJ structures in intestine or skin epithelia, respectively, causing Crohn’s disease–like symptoms in the intestine or psoriasis-like phenotypes on the skin. In patients with Crohn’s disease or psoriasis, junctional Tsc1 levels in epithelial tissues are markedly reduced, concomitant with the TJ structure impairment, suggesting that Tsc1 deficiency may underlie TJ-related diseases. These findings establish an essential role of Tsc1 in the formation of cell junctions and underpin its association with TJ-related human diseases.

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Role of IQGAP1 in endothelial barrier enhancement caused by OxPAPC

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00095.2016 ◽

2016 ◽

Vol 311 (4) ◽

pp. L800-L809 ◽

Cited By ~ 6

Author(s):

Yufeng Tian ◽

Xinyong Tian ◽

Grzegorz Gawlak ◽

Nicolene Sarich ◽

David B. Sacks ◽

...

Keyword(s):

Actin Cytoskeleton ◽

Actin Polymerization ◽

Adherens Junctions ◽

Adherens Junction ◽

Cell Junctions ◽

Endothelial Barrier ◽

Cell Junction ◽

Protective Effects ◽

P120 Catenin

Oxidized 1-palmitoyl-2-arachidonoyl- sn-glycero-3-phosphatidylcholine (OxPAPC) attenuates agonist-induced endothelial cell (EC) permeability and increases pulmonary endothelial barrier function via enhancement of both the peripheral actin cytoskeleton and cell junctions mediated by Rac1 and Cdc42 GTPases. This study evaluated the role for the multifunctional Rac1/Cdc42 effector and regulator, IQ domain containing GTPase-activating protein (IQGAP1), as a molecular transducer of the OxPAPC-mediated EC barrier-enhancing signal. IQGAP1 knockdown in endothelial cells by gene-specific small-interfering RNA abolished OxPAPC-induced enlargement of VE-cadherin-positive adherens junctions, suppressed peripheral accumulation of actin polymerization regulators, namely cortactin, neural Wiskott-Aldrich syndrome protein (N-WASP), and actin-related protein 3, and attenuated remodeling of the peripheral actin cytoskeleton. Inhibition of OxPAPC-induced barrier enhancement by IQGAP1 knockdown was due to suppressed Rac1 and Cdc42 activation. Expression of an IQGAP1 truncated mutant showed that the GTPase regulatory domain of IQGAP1 was essential for the OxPAPC-induced membrane localization of cortactin, adherens junction proteins VE-cadherin and p120-catenin, as well as for EC permeability response. IQGAP1 knockdown attenuated the protective effect of OxPAPC against thrombin-induced cell contraction, cell junction disruption, and EC permeability. These results demonstrate for the first time the role of IQGAP1 as a critical transducer of OxPAPC-induced Rac1/Cdc42 signaling to the actin cytoskeleton and adherens junctions, which promotes cortical cytoskeletal remodeling and EC barrier-protective effects of oxidized phospholipids.

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STAT3 deletion during hematopoiesis causes Crohn's disease-like pathogenesis and lethality: A critical role of STAT3 in innate immunity

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0237137100 ◽

2003 ◽

Vol 100 (4) ◽

pp. 1879-1884 ◽

Cited By ~ 283

Author(s):

T. Welte ◽

S. S. M. Zhang ◽

T. Wang ◽

Z. Zhang ◽

D. G. T. Hesslein ◽

...

Keyword(s):

Innate Immunity ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Critical Role

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Faculty Opinions recommendation of STAT3 deletion during hematopoiesis causes Crohn's disease-like pathogenesis and lethality: a critical role of STAT3 in innate immunity.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1012031.183918 ◽

2003 ◽

Author(s):

Steve Ward

Keyword(s):

Innate Immunity ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Critical Role

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Upregulation of TNF-receptor 2 (p80) in Crohn's disease and critical role of p80 in experimental collitis

Gastroenterology ◽

10.1016/s0016-5085(01)82584-1 ◽

2001 ◽

Vol 120 (5) ◽

pp. A520-A520

Author(s):

M HOLTMANN ◽

M SCHUETZ ◽

P SCHEURICH ◽

P GALLE ◽

M NEURATZ

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Critical Role ◽

Tnf Receptor

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Myosin IIA–mediated forces regulate multicellular integrity during vascular sprouting

Molecular Biology of the Cell ◽

10.1091/mbc.e19-02-0076 ◽

2019 ◽

Vol 30 (16) ◽

pp. 1974-1984 ◽

Cited By ~ 10

Author(s):

Christine Yoon ◽

Colin Choi ◽

Sarah Stapleton ◽

Teodelinda Mirabella ◽

Caroline Howes ◽

...

Keyword(s):

Network Formation ◽

Critical Role ◽

Three Dimensional ◽

Adherens Junction ◽

Cell Junctions ◽

Cell Contractility ◽

Surrounding Matrix ◽

Contractile Forces ◽

Cell Cell

Angiogenic sprouting is a critical process involved in vascular network formation within tissues. During sprouting, tip cells and ensuing stalk cells migrate collectively into the extracellular matrix while preserving cell–cell junctions, forming patent structures that support blood flow. Although several signaling pathways have been identified as controlling sprouting, it remains unclear to what extent this process is mechanoregulated. To address this question, we investigated the role of cellular contractility in sprout morphogenesis, using a biomimetic model of angiogenesis. Three-dimensional maps of mechanical deformations generated by sprouts revealed that mainly leader cells, not stalk cells, exert contractile forces on the surrounding matrix. Surprisingly, inhibiting cellular contractility with blebbistatin did not affect the extent of cellular invasion but resulted in cell–cell dissociation primarily between tip and stalk cells. Closer examination of cell–cell junctions revealed that blebbistatin impaired adherens-junction organization, particularly between tip and stalk cells. Using CRISPR/Cas9-mediated gene editing, we further identified NMIIA as the major isoform responsible for regulating multicellularity and cell contractility during sprouting. Together, these studies reveal a critical role for NMIIA-mediated contractile forces in maintaining multicellularity during sprouting and highlight the central role of forces in regulating cell–cell adhesions during collective motility.

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