Rho proteins play a critical role in cell migration during the early phase of mucosal restitution.

Santos, Marinilce Fagundes dos; McCormack, Shirley A.; Guo, Zhong; Okolicány, J; Zheng, Yi; Johnson, Leonard R.; Tigyi, Gábor

doi:10.1172/jci119515

Cited by 157 publications

(130 citation statements)

References 50 publications

(38 reference statements)

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“…Our results also suggest that LPA-enhanced migration is mediated via PTXsensitive G i and is dependent on actin cytoskeletal integrity. Previous work demonstrated that functional RhoA was necessary for EGF-stimulated migration in IEC (47). Because these upstream elements are all shown here to regulate Pyk2 tyrosine phosphorylation in IEC-18 cells, the findings are compatible with a potential role for Pyk2 in cell migration.…”

Section: Discussionsupporting

confidence: 87%

“…Rho proteins were shown to be critical for cell migration after experimental wounding in both normal (47) and polyamine-deficient IEC-6 cells (41). However, the mechanisms responsible for effecting this response are incompletely understood.…”

Section: Discussionmentioning

confidence: 99%

“…INTESTINAL EPITHELIAL CELL FUNCTIONS, including growth, motility, differentiation, and transport, are regulated by a combination of environmental factors that include peptide signals, bioactive lipids, adhesion to the extracellular matrix, and cell wounding (2,7,13,33,47,55). The nontransformed IEC-18 and IEC-6 intestinal epithelial cell lines, derived from rat small intestinal crypt epithelium (40), have been widely used as a model of epithelial cell proliferation, migration, and differentiation (7,9,33,55).…”

mentioning

confidence: 99%

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ANG II and LPA induce Pyk2 tyrosine phosphorylation in intestinal epithelial cells: role of Ca²⁺, PKC, and Rho kinase

Wu¹,

Chiu

Rozengurt

2002

American Journal of Physiology-Cell Physiology

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2001.-The G protein-coupled receptor agonists angiotensin II (ANG II) and lysophosphatidic acid (LPA) rapidly induce tyrosine phosphorylation of the cytosolic proline-rich tyrosine kinase 2 (Pyk2) in IEC-18 intestinal epithelial cells. The combined Pyk2 tyrosine phosphorylation induced by phorbol 12,13-dibutyrate, a direct agonist of protein kinase C (PKC), and ionomycin, a Ca 2ϩ ionophore, was equal to that induced by ANG II. Inhibition of either PKC or Ca 2ϩ signaling attenuated the effect of ANG II and LPA, although simultaneous inhibition of both pathways failed to completely abolish Pyk2 tyrosine phosphorylation. Cytochalasin D, which disrupts stress fibers, strongly inhibited the response of Pyk2 to ANG II or LPA. The distinct Rho-associated kinase (ROK) inhibitors HA-1077 and Y-27632, as well as the Rho inhibitor Clostridium botulinum C3 exoenzyme, also significantly attenuated ANG II-and LPA-stimulated Pyk2 tyrosine phosphorylation. Simultaneous inhibition of PKC, Ca 2ϩ , and either actin assembly or ROK completely abolished the Pyk2 response. Together, these results show that ANG II and LPA rapidly induce Pyk2 tyrosine phosphorylation in intestinal epithelial cells via separate Ca 2ϩ -, PKC-, and Rho-mediated pathways.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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ANG II and LPA induce Pyk2 tyrosine phosphorylation in intestinal epithelial cells: role of Ca²⁺, PKC, and Rho kinase

Wu¹,

Chiu

Rozengurt

2002

American Journal of Physiology-Cell Physiology

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“…Our results might, therefore, indicate that RhoA is not required for cell motility [see also Banyard et al, 2000]. However, other reports indicate that activation of Rho is necessary for the motile behavior of cells [Stasia et al, 1991;Takaishi et al, 1994;Ridley et al, 1995;Santos et al, 1997;Nobes and Hall, 1999]. This discrepancy may reflect cell type specificity [Hall, 1998] and differences in experimental conditions.…”

Section: Discussionmentioning

confidence: 58%

The role of RhoA in the regulation of cell morphology and motility

Tkach¹,

Bock²,

Berezin³

2005

Cell Motil. Cytoskeleton

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Members of the Rho family of small GTPases are key regulators of the actin cytoskeleton, particularly in relation to the cell shape changes and the adhesion dynamic that drive cell migration. Here, we report the effect of activation or inhibition of the function of RhoA on cell motility and morphology. Both in the presence and the absence of serum, expression of constitutively active RhoA dramatically inhibited L929 fibroblasts' cell motility, and induced a rounding of the cells and a decrease in the number of processes per cell. In contrast, expression of a dominant negative mutant of RhoA had no effect on cell motility or morphology in steady-state conditions with or without serum in the medium. Inhibition of p160ROCK, a kinase effector of RhoA, only partially inhibited cell migration. Conversely, when cells were submitted to a period of serum deprivation followed by addition of serum, inhibition of endogenous RhoA by expression of the dominant negative mutant of RhoA impeded cell motility after serum stimulation. Thus, RhoA activity is required for stimulation of cell locomotion by serum factors. It was also observed that the addition of serum factors to quiescent L929 and NR6wtEGFR fibroblasts resulted in a delayed motility response of several hours compared to the immediately induced morphological changes, indicating the absence of a previously assumed direct correlation between changes in cell motility and cell morphology in response to serum addition. The motility response of L929 and NR6wtEGFR fibroblasts to serum stimulation required protein synthesis. Cell Motil.

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“…Activation of RhoA leads to the subsequent activation of Rho kinase, leading to the formation of stress fibers that contract to pull the cell along the extracellular matrix (28). Although a role for RhoA in enterocyte migration has been postulated, its precise role in mediating enterocyte movement has not been definitively established, and the effects of endotoxin on RhoA activity in enterocytes remain unknown (29). Moreover, the ability of enterocytes to migrate during conditions of high endotoxin exposure, as would be expected during the systemic endotoxemia of NEC, remains unknown.…”

mentioning

confidence: 99%

Endotoxin Inhibits Intestinal Epithelial Restitution through Activation of Rho-GTPase and Increased Focal Adhesions

Çetin

Ford

Sysko

et al. 2004

Journal of Biological Chemistry

130

145

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Diseases of gut inflammation such as neonatal necrotizing enterocolitis (NEC) result after an injury to the mucosal lining of the intestine, leading to translocation of bacteria and endotoxin (lipopolysaccharide). Intestinal mucosal defects are repaired by the process of intestinal restitution, during which enterocytes migrate from healthy areas to sites of injury. In an animal model of NEC, we determined that intestinal restitution was significantly impaired compared with control animals. We therefore sought to determine the mechanisms governing enterocyte migration under basal conditions and after an endotoxin challenge. Here we show that the cytoskeletal reorganization and stress fiber formation required for migration in IEC-6 enterocytes requires RhoA. Enterocytes were found to express the endotoxin receptor Toll-like receptor 4, which served to bind and internalize lipopolysaccharide. Strikingly, endotoxin treatment significantly inhibited intestinal restitution, as measured by impaired IEC-6 cell migration across a scraped wound. Lipopolysaccharide was found to increase RhoA activity in a phosphatidylinositol 3-kinasedependent manner, leading to an increase in phosphorylation of focal adhesion kinase and an enhanced number of focal adhesions. Importantly, endotoxin caused a progressive, RhoA-dependent increase in cell matrix tension/contractility, which correlated with the observed impairment in enterocyte migration. We therefore conclude that endotoxin inhibits enterocyte migration through a RhoA-dependent increase in focal adhesions and enhanced cell adhesiveness, which may participate in the impaired restitution observed in experimental NEC.Necrotizing enterocolitis (NEC) 1 is the leading cause of death from gastrointestinal disease in neonates and is second to respiratory disease as the overall leading cause of morbidity and mortality in this population (1-3). Clinical manifestations of NEC include abdominal distention, feeding intolerance, and systemic sepsis, which result from the destruction of the intestinal barrier (4, 5). Mucosal breakdown may occur as a result of a perinatal insult, such as hypoxia, which allows bacteria and bacterial by-products to breach the normally impermeable mucosal barrier and initiate a local and systemic inflammatory response (4,6,7,9). This causes the release of proinflammatory cytokines, including tumor necrosis factor, platelet-activating factor, nitric oxide, and endotoxin, which lead to further epithelial injury (10 -13). Following mucosal damage, healing occurs initially through the process of epithelial restitution, in which healthy enterocytes adjacent to the sites of injury migrate toward the denuded mucosa to bridge the defect (14 -18). We hypothesize that the intestinal barrier defect in NEC does not result from epithelial injury alone but also from impaired restitution. This paper focuses specifically on the process of enterocyte migration, which is the sine qua non of epithelial restitution and mucosal healing.Although a variety of cytokines may be importan...

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Rho proteins play a critical role in cell migration during the early phase of mucosal restitution.

Cited by 157 publications

References 50 publications

ANG II and LPA induce Pyk2 tyrosine phosphorylation in intestinal epithelial cells: role of Ca²⁺, PKC, and Rho kinase

ANG II and LPA induce Pyk2 tyrosine phosphorylation in intestinal epithelial cells: role of Ca²⁺, PKC, and Rho kinase

The role of RhoA in the regulation of cell morphology and motility

Endotoxin Inhibits Intestinal Epithelial Restitution through Activation of Rho-GTPase and Increased Focal Adhesions

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Rho proteins play a critical role in cell migration during the early phase of mucosal restitution.

Cited by 157 publications

References 50 publications

ANG II and LPA induce Pyk2 tyrosine phosphorylation in intestinal epithelial cells: role of Ca2+, PKC, and Rho kinase

ANG II and LPA induce Pyk2 tyrosine phosphorylation in intestinal epithelial cells: role of Ca2+, PKC, and Rho kinase

The role of RhoA in the regulation of cell morphology and motility

Endotoxin Inhibits Intestinal Epithelial Restitution through Activation of Rho-GTPase and Increased Focal Adhesions

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Product

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ANG II and LPA induce Pyk2 tyrosine phosphorylation in intestinal epithelial cells: role of Ca²⁺, PKC, and Rho kinase

ANG II and LPA induce Pyk2 tyrosine phosphorylation in intestinal epithelial cells: role of Ca²⁺, PKC, and Rho kinase