A CAAX or a CAAL motif and a second signal are sufficient for plasma membrane targeting of ras proteins

Hancock, John F.; Cadwaller, K.; Paterson, Hugh; Marshall, Chris

doi:10.1016/0962-8924(92)90064-t

Cited by 158 publications

(221 citation statements)

References 20 publications

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“…Moreover, adjacent to the CAAX box of racE is a polybasic domain consisting of 6 lysines spread over 11 residues. We postulate that the combination of prenylation with the polybasic domain is probably sufficient to hold racE at the plasma membrane as it has been shown for ras (Hancock et al, 1991). Interestingly, we found that another Dictyostelium rac protein, racC, also localizes to the plasma membrane of the cell.…”

Section: Discussionsupporting

confidence: 71%

Role of Dictyostelium racE in cytokinesis: mutational analysis and localization studies by use of green fluorescent protein.

Larochelle

Vithalani

Lozanne

1997

MBoC

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The small GTPase racE is essential for cytokinesis in Dictyostelium but its precise role in cell division is not known. To determine the molecular mechanism of racE function, we undertook a mutational analysis of racE. The exogenous expression of either wild-type racE or a constitutively active V20racE mutant effectively rescues the cytokinesis deficiency of racE null cells. In contrast, a constitutively inactive N25racE mutant fails to rescue the cytokinesis deficiency. Thus, cytokinesis requires only the activation of racE by GTP and not the inactivation of racE by hydrolysis of GTP. To determine the spatial distribution of racE, we created a fusion protein with GFP at the amino terminus of racE. Remarkably, GFP-racE fusion protein was fully competent to rescue the phenotype of racE null cells and, therefore, must reside in the same location as native racE. We found that GFP-racE localized to the plasma membrane of the cell throughout the entire cell cycle. Furthermore, constitutively active and inactive GFP-racE fusion proteins also localized to the plasma membrane. We mapped the domain required for plasma membrane localization to the carboxyl-terminal 40 amino acids of racE. This domain, however, is not sufficient to confer racE function onto a closely related GTPase. Taken together, these results suggest that racE functions at the cell cortex but it is not involved in determining the timing or placement of the contractile ring.

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Section: Discussionsupporting

confidence: 71%

Role of Dictyostelium racE in cytokinesis: mutational analysis and localization studies by use of green fluorescent protein.

Larochelle

Vithalani

Lozanne

1997

MBoC

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“…The only area of significant sequence divergence between isoforms lies in the Cterminal hypervariable region (HVR) [42]. This short (23-24 aa) stretch terminates with a CAAX motif that undergoes a series of post-translational modifications that promote membrane binding (Figure 1).…”

Section: Compartmentalisation Of Rasmentioning

confidence: 99%

Ras proteins: paradigms for compartmentalised and isoform-specific signalling

Omerovic

Laude

Prior

2007

Cell. Mol. Life Sci.

117

122

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Ras GTPases mediate a wide variety of cellular processes by converting a multitude of extracellular stimuli into specific biological responses including proliferation, differentiation and survival. In mammalian cells, three ras genes encode four Ras isoforms (H-Ras, K-Ras4A, KRas4B and N-Ras) that are highly homologous but functionally distinct. Differences between the isoforms, including their post-translational modifications and intracellular sorting, mean that Ras has emerged as an important model system of compartmentalised signalling and membrane biology. Ras isoforms in different subcellular locations are proposed to recruit distinct upstream and downstream accessory proteins and activate multiple signalling pathways. Here, we summarise data relating to isoform specific signalling, its role in disease and the mechanisms promoting compartmentalised signalling. Further understanding of this field will reveal the role of Ras signalling in development, cellular homeostasis and cancers and may suggest new therapeutic approaches.

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“…Transfer of processed CAAX proteins from the endomembrane to the PM requires a second C-terminal signal immediately upstream of the prenylcysteine-either a series of basic amino acids or cysteine residues that are sites of palmitoylation (Hancock et al, 1990(Hancock et al, , 1991bChoy et al, 1999;Michaelson et al, 2001). Unlike Ras proteins, many Rho proteins are constitutively sequestered in the cytosol through interaction with RhoGDI.…”

Section: Introductionmentioning

confidence: 99%

PostprenylationCAAXProcessing Is Required for Proper Localization of Ras but Not Rho GTPases

Michaelson

Ali

Chiu

et al. 2005

MBoC

154

141

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The CAAX motif at the C terminus of most monomeric GTPases is required for membrane targeting because it signals for a series of three posttranslational modifications that include isoprenylation, endoproteolytic release of the C-terminal-AAX amino acids, and carboxyl methylation of the newly exposed isoprenylcysteine. The individual contributions of these modifications to protein trafficking and function are unknown. To address this issue, we performed a series of experiments with mouse embryonic fibroblasts (MEFs) lacking Rce1 (responsible for removal of the -AAX sequence) or Icmt (responsible for carboxyl methylation of the isoprenylcysteine). In MEFs lacking Rce1 or Icmt, farnesylated Ras proteins were mislocalized. In contrast, the intracellular localizations of geranylgeranylated Rho GTPases were not perturbed. Consistent with the latter finding, RhoGDI binding and actin remodeling were normal in Rce1-and Icmtdeficient cells. Swapping geranylgeranylation for farnesylation on Ras proteins or vice versa on Rho proteins reversed the differential sensitivities to Rce1 and Icmt deficiency. These results suggest that postprenylation CAAX processing is required for proper localization of farnesylated Ras but not geranygeranylated Rho proteins.

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A CAAX or a CAAL motif and a second signal are sufficient for plasma membrane targeting of ras proteins

Cited by 158 publications

References 20 publications

Role of Dictyostelium racE in cytokinesis: mutational analysis and localization studies by use of green fluorescent protein.

Role of Dictyostelium racE in cytokinesis: mutational analysis and localization studies by use of green fluorescent protein.

Ras proteins: paradigms for compartmentalised and isoform-specific signalling

PostprenylationCAAXProcessing Is Required for Proper Localization of Ras but Not Rho GTPases

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