Rho GTPases: Signaling, Migration, and Invasion

Schmitz, Arndt; Govek, Eve-Ellen; Bottner, B.; Aelst, Linda Van

doi:10.1006/excr.2000.5049

Cited by 533 publications

(402 citation statements)

References 113 publications

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“…These results are in agreement with previous observations demonstrating that alendronate inhibits protein tyrosine phosphatases Opas et al, 1997;Schmidt et al, 1996;Skorey et al, 1997). Previous data suggest that the Rho family of GTPases activate kinases that are important in cytoskeletal-mediated changes affecting motility (Mackesky and Hall, 1997;Schmitz et al, 2000). The Rho family of GTPases are post-transcriptionally modified by prenylation.…”

Section: Discussionsupporting

confidence: 93%

Alendronate induces anti-migratory effects and inhibition of neutral phosphatases in UMR106 osteosarcoma cells

Molinuevo

Bruzzone

Cortizo

2007

European Journal of Pharmacology

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Bisphosphonates are nonhydrolysable pyrophosphate analogues that prevent bone loss in several types of cancer. However, the mechanisms of anticancer action of bisphosphonates are not completely known. We have previously shown that nitrogen-containing bisphosphonates directly inhibit alkaline phosphatase of UMR106 rat osteosarcoma cells. In this study, we evaluated the effects of alendronate on the migration of UMR106 osteosarcoma using a model of multicellular cell spheroids, as well as the alendronate effect on neutral phosphatases. Alendronate significantly inhibited the migration of osteoblasts in a dose-dependent manner (10 − 6 -10 − 4 M). This effect was also dependent on calcium availability. The spheroid morphology and distribution of actin fibers were also affected by alendronate treatment. Alendronate dose-dependently inhibited neutral phosphatase activity in cell-free osteoblastic extracts as well as in osteoblasts in culture. Our results show that alendronate inhibits cell migration through mechanisms dependent on calcium, and that seem to involve inhibition of phosphotyrosine-neutral-phosphatases and disassembly of actin stress fibers.

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Section: Discussionsupporting

confidence: 93%

Alendronate induces anti-migratory effects and inhibition of neutral phosphatases in UMR106 osteosarcoma cells

Molinuevo

Bruzzone

Cortizo

2007

European Journal of Pharmacology

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“…Activation of the small GTPase Rho induces stress fiber formation while Rac contributes to the formation of lamellipodia. 33 Our data from actin immunofluorescent staining thus strongly suggest an increase in activation of Rho and Rac in U87-C1 cells. Furthermore, inhibition of MMP activity with the broad-spectrum MMP inhibitor GM6001 in both U87MG and U87-C1 cells diminished overall invasion of both cell types, but did not reduce U87-C1 invasion back to parental baseline levels (data not shown).…”

Section: Discussionsupporting

confidence: 53%

Upregulation of tissue inhibitor of metalloproteinases (TIMP)-2 promotes matrix metalloproteinase (MMP)-2 activation and cell invasion in a human glioblastoma cell line

Jong

Rajasekaran

et al. 2003

Lab Invest

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Local invasiveness is a characteristic feature of glioblastoma that makes surgical resection nearly impossible and accounts in large part for its poor prognosis. To identify mechanisms underlying glioblastoma invasion and motility, we used Transwell invasion chambers to select for a more potently invasive subpopulation of U87MG human glioblastoma cells. The stable population of tumor cells (U87-C1) obtained through this in vitro selection process were three times more invasive than parental U87MG cells and demonstrated faster monolayer wound healing and enhanced radial motility from cell spheroids. This enhanced invasiveness was associated with an 80% increase in matrix metalloproteinase 2 (MMP-2) activation. No differences in expression levels of pro-MMP-2, membrane-type matrix metalloproteinase I (MT1-MMP), or integrin avb3 (mediators of MMP-2 activation) were detected. However, U87-C1 cells exhibited two-fold elevation of tissue inhibitor of metalloproteinases (TIMP)-2 mRNA and protein relative to parental cells. Exogenous addition of comparable levels of purified TIMP-2 to parental U87MG cells increased MMP-2 activation and invasion. Similarly, U87MG cells engineered to overexpress TIMP-2 at the same levels as U87-C1 cells also demonstrated increased MMP-2 activation, indicating that an increase in physiological levels of TIMP-2 can promote MMP-2 activation and invasion in glioblastoma cells. However, exogenous administration or recombinant overexpression of higher amounts of TIMP-2 in U87MG cells resulted in inhibition of MMP-2 activation. These results demonstrate that the complex balance between TIMP-2 and MMP-2 is a critical determinant of glioblastoma invasion, and indicate that increasing TIMP-2 in glioblastoma patients may potentially cause adverse effects, particularly in tumors containing high levels of MT1-MMP and MMP-2.

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“…There is ample evidence that both the NF-kB and RhoA signalling pathways play multiple roles in tumorigenesis, of which cell migration, invasion and escape from apoptosis are important aspects (Schmitz et al, 2000;Basseres and Baldwin, 2006). The finding that a-catulin comprises a part of these two signalling pathways and influences their respective cellular functions is therefore of considerable interest.…”

Section: Discussionmentioning

confidence: 99%

α-Catulin, a Rho signalling component, can regulate NF-κB through binding to IKK-β, and confers resistance to apoptosis

et al. 2007

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Rho GTPases regulate diverse cellular functions including adhesion, cytokinesis and motility, as well as the activity of the transcription factors NF-jB, serum response factor and C/EBP. a-Catulin, an a-catenin-related protein that shares structural similarities with cytoskeletal linker proteins, facilitates Rho signalling by serving as a scaffold for the Rho-specific guanine nucleotide exchange factor Lbc. We report here that a-catulin also interacts with a key component of the NF-jB signalling pathway, namely the IjB kinase (IKK)-b. In co-immunoprecipitations, a-catulin can bind IKK-b and Lbc. Ectopic expression of a-catulin augmented NF-jB activity, promoted cell migration and increased resistance to apoptosis, whereas knockdown experiments showed the opposite effects. Together, these features suggest that a-catulin has tumorigenic potential.

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Rho GTPases: Signaling, Migration, and Invasion

Cited by 533 publications

References 113 publications

Alendronate induces anti-migratory effects and inhibition of neutral phosphatases in UMR106 osteosarcoma cells

Alendronate induces anti-migratory effects and inhibition of neutral phosphatases in UMR106 osteosarcoma cells

Upregulation of tissue inhibitor of metalloproteinases (TIMP)-2 promotes matrix metalloproteinase (MMP)-2 activation and cell invasion in a human glioblastoma cell line

α-Catulin, a Rho signalling component, can regulate NF-κB through binding to IKK-β, and confers resistance to apoptosis

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