Posttranslational processing of the ras superfamily of small GTP-binding proteins

Newman, Christopher M.; Magee, Anthony I.

doi:10.1016/0304-419x(93)90023-6

Cited by 54 publications

(60 citation statements)

References 173 publications

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“…H-Ras normally undergoes a series of sequential modifications commencing with the attachment of a farnesyl moiety to cys-186, followed by proteolytic removal of the three distal amino acids, and finally, carboxyl-methylation of the terminal cysteine [23]. In H-Ras, palmitylation of two upstream cysteines also occurs.…”

Section: Induction Of Cytoplasmic Vacuolation In Human Glioblastoma Cmentioning

confidence: 99%

Activated Ras induces cytoplasmic vacuolation and non-apoptotic death in glioblastoma cells via novel effector pathways

Kaul

Overmeyer

Maltese

2007

Cellular Signalling

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Expression of activated H-Ras induces a unique form of non-apoptotic cell death in human glioblastoma cells and other specific tumor cell lines. The major cytopathological features of this form of death are the accumulation of large phase-lucent, LAMP1-positive, cytoplasmic vacuoles and increased autophagic activity. In this study we sought to determine if induction of cytoplasmic vacuolation a) depends on Ras farnesylation, b) is specific to H-Ras, and c) is mediated by signaling through the major known Ras effector pathways. We find that the unusual effects of activated H-Ras depend on farnesylation and membrane association of the GTPase. Both H-Ras(G12V) and K-Ras4B (G12V) stimulate vacuolation, but activated forms of Cdc42 and RhoA do not. Amino acid substitutions in the Ras effector domain, which are known to selectively impair its interactions with Raf kinase, class-I phosphatidylinositide 3-kinase (PI3K), or Ral nucleotide exchange factors, initially pointed to Raf as a possible mediator of cell vacuolation. However, the MEK inhibitor, PD98059, did not block the induction of vacuoles, and constitutively active Raf-Caax did not mimic the effects of Ras(G12V). Introduction of normal PTEN together with H-Ras(G12V) into U251 glioblastoma cells reduced the PI3K-dependent activation of Akt, but had no effect on vacuolation. Finally, co-expression of H-Ras(G12V) with a dominant-negative form of RalA did not suppress vacuolation. Taken together, the observations indicate that Ras activates non-conventional and perhaps unique effector pathways to induce cytoplasmic vacuolation in glioblastoma cells. Identification of the relevant signaling pathways may uncover specific molecular targets that can be manipulated to activate non-apoptotic cell death in this type of cancer.

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Section: Induction Of Cytoplasmic Vacuolation In Human Glioblastoma Cmentioning

confidence: 99%

Activated Ras induces cytoplasmic vacuolation and non-apoptotic death in glioblastoma cells via novel effector pathways

Kaul

Overmeyer

Maltese

2007

Cellular Signalling

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“…It is increasingly clear that post-translational modifications at the C-termini of G proteins in¯uence hydrophobicity, speci®c protein-protein interactions and intracellular localization (Newman and Magee, 1993). Reversible palmitoylation of p21 K-rasA (Hancock et al, 1989) may a ord a regulatory mechanism which is not available to p21 K-rasB where a polybasic region provides an ionic second signal for membrane binding (Hancock et al, 1990;Jackson et al, 1994).…”

Section: Differential Expression Of K-ras Isoforms S Pells Et Almentioning

confidence: 99%

“…p21 K-rasA and p21 K-rasB are similar, but di er in the 24/25 C-terminal residues. Post-translational modi®cations of this region (Glomset and Farnsworth, 1994;Newman and Magee, 1993) increase the hydrophobicity and membrane binding of p21 ras , which is essential for its function (Jackson et al, 1994;Willumsen et al, 1984). Di erences in these modi®cations between p21 K-rasA and p21 K-rasB may result in selective target interactions and coupling to biochemical pathways (Avruch et al, 1994;Hall, 1994).…”

Section: Introductionmentioning

confidence: 99%

Developmentally-regulated expression of murine K-ras isoforms

et al. 1997

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“…Phosphorylation of ras-related proteins and their relatives as a mechanism of regulation has been tested in a number of cases [34], in which rapl/Krev-l/smgp21 has been implicated in the cAMP-mediated inhibition of platelet metabolism, and appeared to be identical to thrombolamban, a major substrate for PKA in the cells [35][36][37][38]. Phosphorylation of rapl in response to hormones that elevate intracellular cAMP correlates with translocation of rapl from a membrane to a cytosolic fraction [37].…”

Section: Detection Ofneuroj%romin Kinase Activitymentioning

confidence: 99%

Phosphorylation of neurofibromatosis type 1 gene product (neurofibromin) by cAMP‐dependent protein kinase

1996

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The critical function of the neurofibromatosis type 1 lyzed, As a clue to elucidate further the function of neurofi-(NFI) gene product (neurofibromin) is not well defined except bromin, we directed our attention to reports suggesting that that neurofibromin has homology with a family of the GTPaseneurofibromin is heavily phosphorylated on serine and threoactivating proteins (GAPs). In this study, we confirmed that nine resiid~ues in response to growth factors [3,18]. In this neurofibromin is constitutively phosphorylated and detected study, we detected kinase activities which specifically phoskinase activities which specifically phosphorylate the eysteinl phorylate neurofibromin in cell extracts and defined that serine-rich domain and fhe C-terminal domain of the neuroficAMP-dependent protein kinase (PKA) is a candidate for hromin in cell lysate. In vitro and in-gel kinase assays strongly the neurofibromin kinase. indicated that cAMP-dependent protein kinase (PKA) is a candidate for the neurofibromin kinase. The biolo,.ical significance of the phosphorylation of neurofibromin is unclear at present, but we speculate that neurofibromin plays a crucial role in cellular function since it links the two major cellular pathways which are the GAP..rns and PKA-assnciated signals.

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Posttranslational processing of the ras superfamily of small GTP-binding proteins

Cited by 54 publications

References 173 publications

Activated Ras induces cytoplasmic vacuolation and non-apoptotic death in glioblastoma cells via novel effector pathways

Activated Ras induces cytoplasmic vacuolation and non-apoptotic death in glioblastoma cells via novel effector pathways

Developmentally-regulated expression of murine K-ras isoforms

Phosphorylation of neurofibromatosis type 1 gene product (neurofibromin) by cAMP‐dependent protein kinase

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