Guanosine Triphosphatase Activating Protein (GAP) Interacts with the p21
            <i>ras</i>
            Effector Binding Domain

Adari, Hedy; Lowy, Douglas R.; Willumsen, Berthe M.; Der, Channing J.; McCormick, Frank

doi:10.1126/science.2833817

Cited by 508 publications

(273 citation statements)

References 16 publications

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“…Although p120 GAP and NF1/neuro®bromin clearly function as negative regulators of Ras function (Boguski and McCormick, 1993), p120 GAP represented the ®rst candidate Ras e ector (Adari et al, 1988;CaleÂ s et al, 1988). Apparent evidence against an e ector function for Ras GAPs came from studies of Ras e ector domain mutants that impaired p120 or NF1 interactions, yet retained strong focus-forming activity (Marshall and Hettich, 1993).…”

Section: Ras Mediates Its Actions Through Interaction With Multiple Ementioning

confidence: 99%

Increasing complexity of Ras signaling

et al. 1998

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The initial discovery that ras genes endowed retroviruses with potent carcinogenic properties and the subsequent determination that mutated ras genes were present in a wide variety of human cancers, prompted a strong suspicion that the growth-promoting actions of mutated Ras proteins contribute to their aberrant regulation of growth stimulatory signaling pathways. In 1993, a remarkable convergence of experimental observations from genetic analyses of Drosophila, S. cerevisiae and C. elegans as well as biochemical and biological studies in mammalian cells came together to de®ne a clear role for Ras in signal transduction. What emerged was an elegant linear signaling pathway where Ras functions as a relay switch that is positioned downstream of cell surface receptor tyrosine kinases and upstream of a cytoplasmic cascade of kinases that included the mitogen-activated protein kinases (MAPKs). Activated MAPKs in turn regulated the activities of nuclear transcription factors. Thus, a signaling cascade where every component between the cell surface and the nucleus was de®ned and conserved in worms,¯ies and man. This was a remarkable achievement in our e orts to appreciate how the aberrant function of Ras proteins may contribute to the malignant growth properties of the cancer cell. However, the identi®cation of this pathway has proven to be just the beginning, rather than the culmination, of our understanding of Ras in signal transduction. Instead, we now appreciate that this simple linear pathway represents but a minor component of a very complex signaling circuitry. Ras signaling has emerged to involve a complex array of signaling pathways, where cross-talk, feedback loops, branch points and multi-component signaling complexes are recurring themes. The simplest concept of a signaling cascade, where each component simply relays the same message to the next, is clearly not the case. In this review, we summarize our current understanding of Ras signal transduction with an emphasis on new complexities associated with the recognition and/or activation of cellular e ectors, and the diverse array of signaling pathways mediated by interaction between Ras and Ras-subfamily proteins with multiple e ectors.

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Section: Ras Mediates Its Actions Through Interaction With Multiple Ementioning

confidence: 99%

Increasing complexity of Ras signaling

et al. 1998

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“…This protein appears to be involved in growth control and it has been proposed to function not only as the negative regulator of the ras-p21, but also as its downstream effector [39]. Recently, it has been reported that compounds such as arachidonic acid and phosphatidic acid are able to inhibit GAP activity [40].…”

Section: Inhibition Of Gap Activity By Lysolipidsmentioning

confidence: 99%

Elevated levels and mitogenic activity of lysophosphatidylinositol in k‐ras‐transformed epithelial cells

Falasca

Corda

1994

European Journal of Biochemistry

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In cell lines stably (KiKi) or reversibly (Ts) transformed by the k‐ras oncogene originated from a differentiated rat throid line (FRTL5 cells), k‐ras‐induced transformation has been associated with an increased phospholipase A2 activity. Here we provide evidence that this enzymic activity is phosphoinositide specific and leads to the formation of lysophosphatidylinositol. The levels of this lysolipid increased by 2–3‐fold in ras‐transformed cells (KiKi cells and Ts cells at the permissive temperature of 33°C) as compared to differentiated cells (FRTL5) or to Ts cells maintained at 39°C, i.e. at the temperature where ras‐p21, the product of the ras oncogene, is inactive. Since another lysoderivative, lysophosphatidic acid, has been shown to be a mitogen, we have tested whether lysophosphatidylinositol could have a similar activity on thyroid cells. Lysophosphatidylinositol (10–100 μM) induced a 5–10‐fold increase in [3H]thymidine incorporation in both FRTL5 and KiKi cells, whereas lysophosphatidic acid was active only in differentiated cells. Lysophosphatidylinositol (∼25 μM) and lysophosphatidic acid (50–100 μM) acted synergistically with insulin in increasing [3H]thymidine incorporation. Moreover, lysophosphatidylinositol at concentrations three‐fold higher than those found to be mitogenic, inhibited the activity of the GTPase‐activating protein. We conclude that lysophosphatidylinositol is a mitogen that might play a role in the modulation of k‐ras transformed cell proliferation.

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“…The low intrinsic GTPase activity of p21'"'is enhanced by a GTPaseactivating protein (Trahey and McCormick, 1987). Several point mutations in the switch 1 region were reported to destroy the transforming activity of oncogenically activated forms of p2Iri'', which indicated that this part of the protein may constitute the location which regulates the GTPase activity (McCormick, 1989;CalCs et al, 1988;Adari et al, 1988;Sigal et al, 1986). In the a-subunit of heterotrimeric G proteins, where the switch I region was also identified, the role of GTPase-activating protein is apparently fulfilled by a covalently integrated domain (Markby et al, 1993).…”

mentioning

confidence: 99%

Limited Proteolysis and Amino Acid Replacements in the Effector Region ofThermus thermophilusElongation Factor Tu

Zeidler

Schirmer

Egle

et al. 1996

European Journal of Biochemistry

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The effectdr region of the elongation factor Tu (EF-Tu) from Thermus thermophilus was modified by limited prot6lysis or via site-directed mutagenesis. The biochemical properties of the obtained EF-Tu variants were investigated with respect to partial reactions of the functional cycle of EF-Tu. EF-Tu that was cleaved at the ArgS9-Gly60 peptide bond [EF-Tu-(1-59)/EF-Tu-(60-405)] bound GDP, EF-Ts and aminoacyl-tRNA, had normal intrinsic GTPase activity and was active in poly(U)-dependent poly(Phe) synthesis. However, the GTPase activity of EF-Tu-(1-59)/EF-Tu-(60-405) was not stimulated by 7: thermophilus 70s ribosomes, and its GTP-dissociation rate was increased compared with that of intact EF-Tu. EF-Tu cleaved at the Lys52-Ala53 peptide bond has properties similar to EF-Tu-(1-59)/EF-Tu-(60-405). By means of site-directed mutagenesis, Glu5S was replaced by Leu, Glu56 by Ala and Arg59 by Thr in 7: thermophilus EF-Tu. These amino acid substitutions did not substantially affect either the affinity of EF-Tu . GTP for aminoacyl-tRNA or the interactions with GDP, GTP or EF-Ts. Similarly the intrinsic GTPase activity is not influenced. Replacement of Glu56 by Ala led to strong reduction in the ribosome-induced GTPase activity. This effect is specific since replacement of the neighbouring Glu55 by Leu did not affect the ribosome-induced GTPase activity. The results demonstrate that the structure of the effector region of EF-Tu in the vicinity of ArgS9 is important for the control of the GTPase activity by ribosomes.

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Guanosine Triphosphatase Activating Protein (GAP) Interacts with the p21 ras Effector Binding Domain

Cited by 508 publications

References 16 publications

Increasing complexity of Ras signaling

Increasing complexity of Ras signaling

Elevated levels and mitogenic activity of lysophosphatidylinositol in k‐ras‐transformed epithelial cells

Limited Proteolysis and Amino Acid Replacements in the Effector Region ofThermus thermophilusElongation Factor Tu

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