Rac Rho motion Amr Al-Haidari MD MSc

Surgery department

Journal club meeting 20.12.2013

Rac is the actual regulator of RhoA!

Tiam1 and miR-21 are the main

regulators of Rac

FTase regulates RhoA?

Points to be addressed

Small GTPases proteins are involved in cell motility

Small GTPases proteins are involved in cell motility

RhoA Rac Cdc42

Membrane

ruffles and

lamellipodia

filopodia Stress fibers

and focal

adhesion

Endothelial Cell Migration During Angiogenesis. Circ Res. 2007;100:782-794

What is the relation between Rho and Rac?

Jacobson, Dudek, Birukov, et al. Simvastatin Alters EC Function and Gene Expression Am. J. Respir. Cell Mol. Biol. 2004

Simvastatin mode of Rho/Rac regulation..!

Ruqin Kou et al. Regulation of Rac1 by simvastatin in endothelial cells: differential roles of AMP-activated protein kinase and calmodulin-dependent kinase kinase-beta. J Biol Chem. 2009 May 29; 284

Statin

increases Rac

activity

Mevalonate and

isopernoids

decrease Rac

activity

Was it due to RhoA or Rac??

Data Normalized against beta actin and calibrated against Untreated control cells

0

0.5

1

1.5

2

2.5

Simv treated cells

CCL17 treated cells Fold

ch

ange

s

Rac1 mRNA

RhoA mRNA

Simvastatin

increases Rac and

decreases RhoA

Reciprocal relation

ship!

% o

f m

igra

ted

cel

ls

__ Vehicle 10 20

*

*

#

CCL17+FTI-277 µM

Pirkko L. Harkonen et al. Inhibition of GGTase-I and FTase disrupts cytoskeletal organization of human PC-3 prostate cancer cells. Cell Biol. Int. (2010) 34, 815–826

What about FTi-277?

RhoA mRNA

?

Ras status in cancers? 30% mutated

miR-21

?

FTi

TIAM1

GGTi

Journal of the National Cancer Institute feb.2013

Serum miR-21 as a Diagnostic and Prognostic Biomarkerin Colorectal Cancer

Charisa et as. miR-21 and miR-31 Converge on TIAM1 to Regulate Migration and Invasion of Colon Carcinoma Cells. J Biol Chem. 2010 November 12; 285

Upregulation of miR-21 increases migration and invasion of colon cancer cells

Charisa et as. miR-21 and miR-31 Converge on TIAM1 to Regulate Migration and Invasion of Colon Carcinoma Cells. J Biol Chem. 2010 November 12; 285

Rho/Rac Ratio

If RhoA ˃ Rac Active migration

If Rac ˃ RhoA Active invasion or ?

RhoA ᾱ 1/Rac

miR-21 Tiam1 Rac RhoA

Cell migration control?

FTase

?

In conclusion, our novel findings suggest that Rac1 signaling is a key component in the pathophysiology of acute lung injury triggered by streptococcal M1 protein. Inhibition of Rac1 activity reduces M1 protein-provoked neutrophil infiltration in the lung via inhibition of CXC chemokine formation in alveolar macrophages. These results suggest that targeting Rac1 signaling might be a useful approach in order to protect respiratory function in streptococcal infections.

Streptococcal M1 Protein Triggers Farnesyltransferase-Dependent Formation of CXC Chemokines in Alveolar Macrophages and Neutrophil Infiltration of the Lungs Songen Zhanga, Milladur Rahmana, Su Zhanga, Bengt Jeppssona, Heiko Herwaldb and Henrik Thorlaciusa Our novel findings demonstrate that farnesyltransferase is an important regulator of neutrophil-mediated acute lung injury triggered by streptococcal M1protein. Moreover, we demonstrate that inhibition of farnesyltransferase abolishes the macrophage dependent generation of CXC chemokines in response toM1protein challenge. Thus, we conclude that these farnesyltransferasedependent mechanisms may, at least in part, help to clarify the beneficial effects exerted by statins and that targeting farnesyltransferase activity might be useful in order to protect against respiratory failure in streptococcal infections.

Targeting Rac1 Signaling Inhibits Streptococcal M1 Protein-Induced CXC Chemokine Formation, Neutrophil Infiltration and Lung Injury Songen Zhang1, Milladur Rahman1, Su Zhang1, Lei Song1, Heiko Herwald2, Henrik Thorlacius