RhoE inhibits 4E-BP1 phosphorylation and eIF4E function impairing cap-dependent translation.
The Rho GTPase family member RhoE inhibits RhoA/ROCK signaling to promote actin stress fiber and focal adhesion disassembly. We have previously reported that RhoE also inhibits cell cycle progression and Ras-induced transformation, specifically preventing cyclin D1 translation. Here we investigate the molecular mechanisms underlying those observations. RhoE inhibits the phosphorylation of the translational repressor 4E-BP1 in response to extracellular stimuli. However, RhoE does not affect the activation of mTOR, the major kinase regulating 4E-BP1 phosphorylation, as indicated by the phosphorylation levels of the mTOR substrate S6K, the dynamics of mTOR/Raptor association, and the observation that RhoE, as opposed to rapamycin, does not impair cellular growth. Interestingly, RhoE prevents the release of the eukaryotic initiation factor eIF4E from 4E-BP1, inhibiting cap-dependent translation. Accordingly, RhoE also inhibits the expression and the transcriptional activity of the eIF4E target c-Myc. Consistent with its crucial role in cell proliferation, we show that eIF4E can rescue both cell cycle progression and Ras-induced transformation in RhoE-expressing cells, indicating that the inhibition of eIF4E function is critical to mediate the anti-proliferative effects of RhoE.
Ludwig Institute for Cancer Research, University College London, W1W7BS London, United Kingdom. priam.villalonga@uib.es
Priam
P
Villalonga
Silvia
S
Fernández de Mattos
Anne J
AJ
Ridley
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002522:Chlorocebus aethiops; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000378:metabolism*; D039642:Eukaryotic Initiation Factors; D022001:Focal Adhesions / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis / Q000502:physiology*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012315:RNA Caps / Q000235:genetics / Q000378:metabolism*; D000076223:Regulatory-Associated Protein of mTOR; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D022502:Stress Fibers / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C530104:CCND1 protein, human; D002352:Carrier Proteins; C530105:Ccnd1 protein, mouse; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; C499527:Eif4ebp1 protein, mouse; D039561:Eukaryotic Initiation Factor-4E; D039642:Eukaryotic Initiation Factors; C489427:MYC protein, human; D010750:Phosphoproteins; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D012315:RNA Caps; C463659:RPTOR protein, human; D000076223:Regulatory-Associated Protein of mTOR; C540162:Rptor protein, mouse; C066737:RHOA protein, human; D019938:Cyclin D1; D017853:Phosphotransferases (Alcohol Group Acceptor); C546842:MTOR protein, human; C546843:mTOR protein, mouse; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D054460:rho-Associated Kinases; C513341:Rnd3 protein, mouse; C508705:RND3 protein, human; C526380:RhoA protein, mouse; D018631:ras Proteins; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein