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bFGF Regulates PI3-Kinase-Rac1-JNK Pathway and Promotes Fibroblast Migration in Wound Healing
, 2010
"... Fibroblast proliferation and migration play important roles in wound healing. bFGF is known to promote both fibroblast proliferation and migration during the process of wound healing. However, the signal transduction of bFGF-induced fibroblast migration is still unclear, because bFGF can affect both ..."
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Fibroblast proliferation and migration play important roles in wound healing. bFGF is known to promote both fibroblast proliferation and migration during the process of wound healing. However, the signal transduction of bFGF-induced fibroblast migration is still unclear, because bFGF can affect both proliferation and migration. Herein, we investigated the effect of bFGF on fibroblast migration regardless of its effect on fibroblast proliferation. We noticed involvement of the small GTPases of the Rho family, PI3-kinase, and JNK. bFGF activated RhoA, Rac1, PI3-kinase, and JNK in cultured fibroblasts. Inhibition of RhoA did not block bFGF-induced fibroblast migration, whereas inhibition of Rac1, PI3-kinase, or JNK blocked the fibroblast migration significantly. PI3kinase-inhibited cells down-regulated the activities of Rac1 and JNK, and Rac1-inhibited cells down-regulated JNK activity, suggesting that PI3-kinase is upstream of Rac1 and that JNK is downstream of Rac1. Thus, we concluded that PI3-kinase, Rac1, and JNK were essential for bFGF-induced fibroblast migration, which is a novel pathway of bFGF-induced cell migration.
A mouse model for the study of recurrent corneal epithelial erosions: Į9ȕ1 integrin implicated in progression of the disease. Invest Ophthalmol Vis Sci 45
, 2004
"... PURPOSE. To describe an in vivo mouse model for the study of recurrent corneal erosion syndrome (RCES) in mice and to characterize the changes in ␣9 integrin expression during wound healing. METHODS. Corneal epithelial debridement wounds of two sizes (1.5 and 2.5 mm) were made on the ocular surface ..."
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PURPOSE. To describe an in vivo mouse model for the study of recurrent corneal erosion syndrome (RCES) in mice and to characterize the changes in ␣9 integrin expression during wound healing. METHODS. Corneal epithelial debridement wounds of two sizes (1.5 and 2.5 mm) were made on the ocular surface of BALB/c mice and were evaluated at various times after wounding. Corneas were processed either as whole mounts and stained with propidium iodide and an antibody against ␣9 integrin or for bromodeoxyuridine analyses of cell proliferation. A separate study involved analyses of corneal wound healing over time in individual mice with large and small debridement wounds. Mice were anesthetized once per week and their corneas stained with fluorescein to assess the quality of the corneal epithelium. After 6 weeks, mice were killed and eyes processed for study by immunofluorescence in either whole mounts or frozen sections. RESULTS. Whole mount confocal microscopy showed open wounds on the ocular surface of mice at 1 and 2 weeks after large wounds were created, but not after small wounds. In addition, ␣9 integrin was upregulated during healing, and changes were observed in ␣9 integrin localization at the limbus with large wounds but not with small wounds. Although only 1 of 16 corneas with small wounds had erosions at 1 and 2 weeks, 11 of 16 with large wounds had erosions. However, by 6 weeks, 13 of 16 eyes showed signs of erosion whether wounds were small or large. With large wounds, RCES corneas frequently showed numerous goblet cells adjacent to a limbus lacking ␣9 integrin. Corneas from mice with documented RCES showed both retention of ␣9 integrin and tenascin-C expression at the anterior stromal-epithelial interface as well as impaired relocalization of ␣31 integrin to the basement membrane zone. CONCLUSIONS. These data show that spontaneous recurrent corneal erosions occur in a mouse model after manual creation of a single wound by debridement. Differences between the healing of small (1.5 mm) and large (2.5 mm) wounds were observed. Large wounds often resulted in the presence of goblet cells on the central cornea and a loss of ␣9 integrin at the limbus. Small wounds never showed differences in the localization of ␣9 integrin at the limbus, and no goblet cells were observed in the central cornea. More studies are needed to understand the causes of erosions in these mice. (Invest Ophthalmol Vis Sci.
Extracellular signal-regulated kinase promotes Rho-dependent focal adhesion formation by suppressing p190A
, 2010
"... Cell migration is critical for normal development and for pathological processes including cancer cell metastasis. Dynamic remodeling of focal adhesions and the actin cytoskeleton are crucial determinants of cell motility. The Rho family and the mitogen-activated protein kinase (MAPK) module consist ..."
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Cell migration is critical for normal development and for pathological processes including cancer cell metastasis. Dynamic remodeling of focal adhesions and the actin cytoskeleton are crucial determinants of cell motility. The Rho family and the mitogen-activated protein kinase (MAPK) module consisting of MEK– extracellular signal-regulated kinase (ERK) are important regulators of these processes, but mechanisms for the integration of these signals during spreading and motility are incompletely understood. Here we show that ERK activity is required for fibronectin-stimulated Rho-GTP loading, Rho-kinase function, and the maturation of focal adhesions in spreading cells. We identify p190A RhoGAP as a major target for ERK signaling in adhesion assembly and identify roles for ERK phosphorylation of the C terminus in p190A localization and activity. These observations reveal a novel role for ERK signaling in adhesion assembly in addition to its established role in adhesion disassembly. Cell migration is a highly coordinated process essential for physiological and pathological processes (69). Signaling through Rho family GTPases (e.g., Rac, Cdc42, and Rho) is crucial for cell migration. Activated Rac and Cdc42 are involved in the production of a dominant lamellipodium and filopodia, respec-
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"... The interaction of cells with the surrounding extracellular matrix (ECM) is a key regulatory mechanism controlling essential cellular functions and differentiation (Cukierman et al., 2002; Humphries et al., 2004; Larsen et al., 2006). Fibroblasts are resident cells in ..."
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The interaction of cells with the surrounding extracellular matrix (ECM) is a key regulatory mechanism controlling essential cellular functions and differentiation (Cukierman et al., 2002; Humphries et al., 2004; Larsen et al., 2006). Fibroblasts are resident cells in
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"... The interaction of cells with the surrounding extracellular matrix (ECM) is a key regulatory mechanism controlling essential cellular functions and differentiation (Cukierman et al., 2002; Humphries et al., 2004; Larsen et al., 2006). Fibroblasts are resident cells in ..."
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The interaction of cells with the surrounding extracellular matrix (ECM) is a key regulatory mechanism controlling essential cellular functions and differentiation (Cukierman et al., 2002; Humphries et al., 2004; Larsen et al., 2006). Fibroblasts are resident cells in
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"... The interplay between pathogen-encoded virulence factors and host cell signaling networks is critical for both the establishment and clearance of microbial infections. Yersinia pseudotuberculosis is an extracellular, Gram-negative bacteria ..."
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The interplay between pathogen-encoded virulence factors and host cell signaling networks is critical for both the establishment and clearance of microbial infections. Yersinia pseudotuberculosis is an extracellular, Gram-negative bacteria
The Coca-Cola Company
"... I would like to thank the following members of the former Radhakrishna Lab for numerous helpful discussions during the course of this project: Dr. Nikhil Urs, Dr. Kymry Jones, and Jennifer Hurst-Kennedy. I would especially like to thank Dr. Urs for all of his assistance during the course of this pro ..."
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I would like to thank the following members of the former Radhakrishna Lab for numerous helpful discussions during the course of this project: Dr. Nikhil Urs, Dr. Kymry Jones, and Jennifer Hurst-Kennedy. I would especially like to thank Dr. Urs for all of his assistance during the course of this project. I thank all of my committee
4288 | N. Balanis et al. Molecular Biology of the Cell
"... β3 Integrin–EGF receptor cross-talk activates p190RhoGAP in mouse mammary gland epithelial cells ..."
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β3 Integrin–EGF receptor cross-talk activates p190RhoGAP in mouse mammary gland epithelial cells
Integrin Signaling through Arg Activates p190RhoGAP by Promoting Its Binding to p120RasGAP and Recruitment to
, 2006
"... The Rho family GTPases RhoA (Rho), Rac1, and Cdc42 are essential effectors of integrin-mediated cell attachment and spreading. Rho activity, which promotes formation of focal adhesions and actin stress fibers, is inhibited upon initial cell attachment to allow sampling of the new adhesive environmen ..."
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The Rho family GTPases RhoA (Rho), Rac1, and Cdc42 are essential effectors of integrin-mediated cell attachment and spreading. Rho activity, which promotes formation of focal adhesions and actin stress fibers, is inhibited upon initial cell attachment to allow sampling of the new adhesive environment. The Abl-related gene (Arg) tyrosine kinase mediates adhesion-dependent inhibition of Rho through phosphorylation and activation of the Rho inhibitor p190RhoGAP-A (p190). p190 phosphorylation promotes its binding to p120RasGAP (p120). Here, we elucidate the mechanism by which p120 binding regulates p190 activation after adhesion. We show that p190 requires its p120-binding domain to undergo Arg-dependent activation in vivo. However, p120 binding does not activate p190RhoGAP activity in vitro. Instead, activation of p190 requires recruitment to the cell periphery. Integrin-mediated adhesion promotes relocalization of p190 and p120 to the cell periphery in wild-type fibroblasts, but not in arg/ fibroblasts. A dominant-negative p120 fragment blocks p190:p120 complex formation, prevents activation of p190 by adhesion, and disrupts the adhesion-dependent recruitment of p190 to the cell periphery. Our results demonstrate that integrin signaling through Arg activates p190 by promoting its association with p120, resulting in recruitment of p190 to the cell periphery where it inhibits Rho.
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"... In multicellular organisms, cell migration is essential to normal development, and is required throughout life for responses to tissue damage and infection. Cell migration also occurs in chronic human diseases; in cancer, atherosclerosis and chronic ..."
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In multicellular organisms, cell migration is essential to normal development, and is required throughout life for responses to tissue damage and infection. Cell migration also occurs in chronic human diseases; in cancer, atherosclerosis and chronic
