Involvement of the Small GTPase Rho in Integrin-mediated Activation of Mitogen-activated Protein Kinase

Renshaw, Mark W.; Toksoz, Deniz; Schwartz, Martin A.

doi:10.1074/jbc.271.36.21691

Cited by 133 publications

(94 citation statements)

References 30 publications

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“…It has been suggested that Rho could be involved in integrininduced activation of ERK2 in fibroblasts (43). Our data further establish that RhoA/ROCK acts as an upstream regulator of the ERK cascade to induce cell proliferation in response to US stimulation in primary human skin fibroblasts.…”

Section: Discussionsupporting

confidence: 60%

Molecular Mechanisms of Low Intensity Pulsed Ultrasound in Human Skin Fibroblasts

Zhou

Schmelz

Seufferlein

et al. 2004

Journal of Biological Chemistry

231

168

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Soluble factors such as polypeptide growth factors, mitogenic lipids, inflammatory cytokines, and hormones are known regulators of cell proliferation. However, the effect of mechanical stimuli on cell proliferation is less well understood. Here we examined the effect of low intensity pulsed ultrasound (US), which is used to promote wound healing, on the proliferation of primary human foreskin fibroblasts and the underlying signaling mechanisms. We show that a single 6 -11-min US stimulation increases bromodeoxyuridine incorporation. In addition, an increase in the total cell number is observed after sequential US stimulation. US induced stress fiber and focal adhesion formation via activation of Rho. We further observed that US selectively induced activation of extracellular signal-regulated kinase (ERK) 1/2. Inhibition of Rho-associated coiled-coil-containing protein kinase (ROCK) prevented US-induced ERK1/2 activation, demonstrating that the Rho/ROCK pathway is an upstream regulator of ERK activation in response to US. Consequently, activation of ROCK and MEK-1 was required for US-induced DNA synthesis. Finally, an integrin ␤ 1 blocking antibody as well as a RGD peptide prevented US-induced DNA synthesis. In addition, US slightly increased phosphorylation of Src at Tyr 416 , and Src activity was found to be required for ERK1/2 activation in response to US. In conclusion, our data demonstrate for the first time that US promotes cell proliferation via activation of integrin receptors and a Rho/ROCK/Src/ERK signaling pathway.Signal transduction mechanisms of receptor tyrosine kinase or heptahelical receptors have been studied extensively over the last years. However, the effect of acoustic pulsed energy on cell growth and the signal transduction mechanisms induced by this type of mechanical stimulation are not well understood. Previous studies have shown that mechanical stress such as stretch and shear stress can induce DNA synthesis in certain cell types and that extracellular signal-regulated kinase (ERK) 1 1/2 can be activated by mechanical stress (1-4).Low intensity pulsed ultrasound (US) is a special type of acoustic pulsed energy that is increasingly used as a supplementary therapy to promote bone and wound healing (5). US, transmitting as an acoustic pressure wave and applying mechanical stress indirectly to the tissues, has been reported to promote osteogenesis and protein synthesis, calcium uptake, and DNA synthesis in different cells (6 -9). US-induced DNA synthesis seems cell type-dependent; US promotes DNA synthesis in human osteoblasts, gingival fibroblasts, and periosteal cells (6, 8, 10), but not in chondrocytes (11,12). However, the molecular mechanisms by which US induces DNA synthesis or even cell proliferation are largely unknown.There is growing evidence that integrins are promising candidates for sensing extracellular matrix-derived mechanical stimuli and converting them into biochemical signals (13,14). Integrin-associated signaling pathways include an increase in tyrosine phosphorylation of...

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Section: Discussionsupporting

confidence: 60%

Molecular Mechanisms of Low Intensity Pulsed Ultrasound in Human Skin Fibroblasts

Zhou

Schmelz

Seufferlein

et al. 2004

Journal of Biological Chemistry

231

168

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“…Indeed, induction of MAPK activity and cell proliferation occur in fibroblasts only when cells adhere to and spread on tenascin using αvβ3 and α9β1 integrins, whereas adhesion to tenascin via the αvβ6 integrin, which does not support cell spreading, fails to induce MAPK activity and cell proliferation [50]. Similarly, although growth factors can activate the upstream mediators Ras and Raf in non-transformed cells cultured in suspension, the subsequent activation of ERK2 occurs only when cells adhere to fibronectin [88]. Together these results support the hypothesis that ECM-directed cell morphology and associated cytoskeletal changes may spatially co-ordinate cell receptors and intracellular signalling molecules, thereby permitting upstream effectors, including focal adhesion proteins such as FAK, Ras and Raf, to couple with their downstream targets, including MAPKs (Figure 2).…”

Section: How Does Cell Shape Influence Intracellular Signalling ?mentioning

confidence: 99%

Extracellular matrix and integrin signalling: the shape of things to come

Boudreau

Jones

1999

Biochemical Journal

421

139

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The extracellular matrix (ECM) and integrins collaborate to regulate gene expression associated with cell growth, differentiation and survival. Biochemical and molecular analyses of integrin signalling pathways have uncovered several critical cytoplasmic proteins that link the ECM and integrins to intracellular pathways that may contribute to anchorage-dependent growth. A large body of evidence now indicates that the non-receptor protein kinases focal adhesion kinase (FAK) and specific members of the mitogen-activated protein kinases (MAPKs), including the extracellular-signal-regulated kinases (ERKs), mediate these ECM- and integrin-derived signalling events. However, little is known about how FAK and MAPKs contribute to biological processes other than cell proliferation or migration. In addition, remarkably little is known concerning the signalling events that occur in cells that adhere to complex multivalent extracellular matrices via multiple integrin receptors. Given the stringent requirement for attaining a proper morphology in ECM/integrin-directed cell behaviour, it is still not clear how cell shape and tissue architecture impact upon intracellular signalling programmes involving FAK and MAPKs. However, the recent discovery that members of the Rho family of small GTPases are able to regulate ECM/integrin pathways that modulate both cell shape and intracellular signalling provides new insights into how cell morphology and signal transduction become integrated, especially within three-dimensional differentiated tissues.

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“…Furthermore they showed that injection of anti-PIP 2 antibodies into ®broblasts inhibited LPA/Rhoinduced stress ®bers and focal adhesion formation, suggesting a role for PIP 2 in focal adhesion and stress ®ber assembly. Second, dominant negative Rho has been shown to partially suppress the activation of ERK in response to ligation of integrins, suggesting that a Rho regulated pathway is necessary for the full activation of ERK following integrin mediated cell adhesion (Renshaw et al, 1996).…”

Section: Role Of Rho Family Of Proteins In Focal Adhesion Assemblymentioning

confidence: 99%

Signaling by integrin receptors

Kumar¹

1998

Oncogene

256

181

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Adhesive interactions are critical for the proliferation, survival and function of all cells. Integrin receptors as the major family of adhesion receptors have been the focus of study for more than a decade. These studies have tremendously enhanced our understanding of the integrin-mediated adhesive interactions and have unraveled novel integrin functions in cell survival mechanisms and in the activation of divergent signaling pathways. The signals from integrin receptors are integrated from those originating from growth factor receptors in order to organize the cytoskeleton, stimulate cell proliferation and rescue cells from matrix detachment-induced programmed cell death. These functions are critical in the regulation of multiple processes such as tissue development, in¯ammation, angiogenesis, tumor cell growth and metastasis and programmed cell death.

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Involvement of the Small GTPase Rho in Integrin-mediated Activation of Mitogen-activated Protein Kinase

Cited by 133 publications

References 30 publications

Molecular Mechanisms of Low Intensity Pulsed Ultrasound in Human Skin Fibroblasts

Molecular Mechanisms of Low Intensity Pulsed Ultrasound in Human Skin Fibroblasts

Extracellular matrix and integrin signalling: the shape of things to come

Signaling by integrin receptors

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