INT228103

Context Info Confidence 0.67 First Reported 2007 Last Reported 2010 Negated 2 Speculated 0 Reported most in Body Documents 25 Total Number 48 Disease Relevance 18.92 Pain Relevance 0.57

intracellular (Rac1) enzyme binding (Rac1) GTPase activity (Rac1) cytoplasm (Rac1) cell proliferation (Rac1) cell motility (Rac1)

Anatomy Link Frequency endothelial cell 5 bar 2 tube 1 B cells 1 brain 1 Rac1 (Mus musculus)

Pain Link Frequency Relevance Heat cINOD 25 98.88 metalloproteinase 1 98.86 Inflammation 142 98.40 ischemia 38 89.20 Arthritis 26 39.00 abdominal pain 24 38.56 headache 26 37.48 cytokine 33 30.72 Inflammatory response 3 21.44 antagonist 20 5.00

Disease Link Frequency Relevance Heat Mevalonate Kinase Deficiency 1392 99.84 Stress 69 99.12 Pathologic Neovascularization 57 99.10 Targeted Disruption 130 98.72 INFLAMMATION 162 98.64 Adhesions 44 98.10 Cancer 1690 97.76 Pressure And Volume Under Development 2 97.44 Apoptosis 56 96.64 Hypersensitivity 94 96.40

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Its involvement in the function of endothelial cells has also been illustrated by the activation of Rac1 under flow and shear stress [23].

Positive_regulation (activation) of Rac1 in endothelial cells associated with stress

1) Confidence 0.67 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2842301 Disease Relevance 0.53 Pain Relevance 0.04

Several studies have shown that VEGF-mediated endothelial cell migration in 2D involves activation of Rac1 [38], [39], [40] and our data are in line with these observations.

Positive_regulation (activation) of Rac1 in endothelial cell

2) Confidence 0.67 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2842301 Disease Relevance 0.17 Pain Relevance 0

Regarding proliferation, our results corroborate the findings that increased Rac1 activity correlates with enhanced endothelial proliferation, since the elevated Rac1-activity in ?

Positive_regulation (elevated) of Rac1

3) Confidence 0.48 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2842301 Disease Relevance 0.30 Pain Relevance 0

To verify that tamoxifen treatment of Rac1 flox/flox PDGFB-iCreER endothelial cells induced Rac1-deletion, endothelial cells and non-endothelial cells were isolated from Rac1 flox/flox PDGFB-iCreER mice and treated with tamoxifen (OHT) or ethanol (vehicle) in culture.

Positive_regulation (induced) of Rac1 in endothelial cells

4) Confidence 0.48 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2842301 Disease Relevance 0.57 Pain Relevance 0

This vector allows tissue-specific activation of Rac1 short hairpin RNA (shRNA) in Cre-expressing cells in vivo.

Positive_regulation (activation) of Rac1

5) Confidence 0.48 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2842301 Disease Relevance 0.58 Pain Relevance 0

In contrast, recent studies have suggested a positive role for Rac1 in endothelial cell function.

Positive_regulation (role) of Rac1 in endothelial cell

6) Confidence 0.48 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2842301 Disease Relevance 0.53 Pain Relevance 0.04

Our data also illustrate that the requirement for Rac1 in 3D versus 2D endothelial cell migration is different.

Positive_regulation (requirement) of Rac1 in endothelial cell

7) Confidence 0.48 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2842301 Disease Relevance 0.14 Pain Relevance 0

RhoA, Cdc42 and Rac1 can be activated when GTP-bound, and inactivated, when GDP-bound.

Positive_regulation (activated) of Rac1

8) Confidence 0.48 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2842301 Disease Relevance 0.82 Pain Relevance 0

Although recent work has shown that molecules such as RhoG can compensate for Rac-1 [51] there is also evidence that this depends on specific signaling cascades and is not always the case [52].

Positive_regulation (compensate) of Rac-1

9) Confidence 0.48 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2842301 Disease Relevance 0.07 Pain Relevance 0.07

Rac1 is not required for VEGF-mediated angiogenesis in wild-type mice but is in ?

Neg (not) Positive_regulation (required) of Rac1

10) Confidence 0.48 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2842301 Disease Relevance 0.34 Pain Relevance 0

Vania Braga, Imperial College, London, UK), was used to pull down active Rac1 and Cdc42 from MLEC cell lysates transfected with scrambled or Rac1 siRNA.

Positive_regulation (active) of Rac1

11) Confidence 0.48 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2842301 Disease Relevance 0 Pain Relevance 0

Given that VEGF is a key positive regulator of pathological angiogenesis and that VEGF/VEGFR2 signalling is known to activate Rac1 in vitro, we tested the effect of endothelial-specific Rac1-depletion on VEGF-mediated neovascularization in vivo.

Positive_regulation (activate) of Rac1 associated with pathologic neovascularization

12) Confidence 0.48 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2842301 Disease Relevance 0.27 Pain Relevance 0

To confirm that the observed effect of simvastatin on RhoA and Rac1 activation was due to a shortage of GGPP, we studied the effect of GGTI, an inhibitor of geranylgeranyl transferase, on localization and activation of RhoA and Rac1 and found that GGTI had a similar effect as simvastatin.

Positive_regulation (activation) of Rac1

13) Confidence 0.46 Published 2010 Journal J Inherit Metab Dis Section Body Doc Link PMC2946549 Disease Relevance 0.28 Pain Relevance 0

After treatment with GGTI, Rac1 was also activated in MKD cells; however, no Rac1 activation was detected in control cells (Fig. 2j).

Neg (no) Positive_regulation (activation) of Rac1 associated with mevalonate kinase deficiency

14) Confidence 0.46 Published 2010 Journal J Inherit Metab Dis Section Body Doc Link PMC2946549 Disease Relevance 0.37 Pain Relevance 0

In summary, we showed that protein isoprenylation in MKD cells is more sensitive to inhibition by simvastatin than in control cells, resulting in an increased, ectopic activation of soluble RhoA and Rac1 in MKD cells.

Positive_regulation (activation) of Rac1 associated with mevalonate kinase deficiency

15) Confidence 0.46 Published 2010 Journal J Inherit Metab Dis Section Body Doc Link PMC2946549 Disease Relevance 1.09 Pain Relevance 0.08

The relative increase in active RhoA was larger than the relative increase in active Rac1 (Fig. 1e, j).

Positive_regulation (increase) of Rac1

16) Confidence 0.46 Published 2010 Journal J Inherit Metab Dis Section Body Doc Link PMC2946549 Disease Relevance 0.18 Pain Relevance 0

Because small GTPases depend on isoprenylation for their proper signalling function, we studied the effect of MK deficiency on isoprenylation (i.e., geranylgeranylation) and activation of the two small GTPases, RhoA and Rac1.

Positive_regulation (activation) of Rac1

17) Confidence 0.46 Published 2010 Journal J Inherit Metab Dis Section Body Doc Link PMC2946549 Disease Relevance 0.51 Pain Relevance 0.04

After treatment with GGTI, Rac1 was also activated in MKD cells; however, no Rac1 activation was detected in control cells (Fig. 2j).

Positive_regulation (activated) of Rac1 associated with mevalonate kinase deficiency

18) Confidence 0.46 Published 2010 Journal J Inherit Metab Dis Section Body Doc Link PMC2946549 Disease Relevance 0.37 Pain Relevance 0

Incubation with GGTI led to a reduction in membrane-bound RhoA and Rac1 that was similar for both control and MKD cells (Fig. 2b, g) and, in parallel, an increase in the levels of soluble RhoA and Rac1 (Fig. 2c and 2h).

Positive_regulation (increase) of Rac1 associated with mevalonate kinase deficiency

19) Confidence 0.46 Published 2010 Journal J Inherit Metab Dis Section Body Doc Link PMC2946549 Disease Relevance 0.30 Pain Relevance 0

The increase in total cellular levels of active RhoA and Rac1 due to simvastatin appears primarily, if not solely, caused by activation of soluble RhoA and Rac1 and not membrane-bound RhoA and Rac1.

Positive_regulation (increase) of Rac1

20) Confidence 0.46 Published 2010 Journal J Inherit Metab Dis Section Body Doc Link PMC2946549 Disease Relevance 0.11 Pain Relevance 0

General Comments

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