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1.
Ras-GAP (GTPase activating protein) is a regulatory protein that stimulates the intrinsic guanosine triphosphatase (GTPase) activity of the proto-oncogene product p21ras. A domain of the neurofibromatosis gene product (NF1) that has sequence similarity to the catalytic domain of Ras-GAP and to yeast IRA gene products also has a specific stimulatory activity toward p21ras GTPase. Arachidonic acid and phosphatidic acid inactivate GAP, but no agents have been identified that stimulate GAP and thereby switch p21ras off. With the use of recombinant Ha-c-Ras and Ras-GAP, NF1, and GAP catalytic domains, it was found that prostaglandins PGF2 alpha and PGA2 stimulated Ras-GAP and that prostacyclin PGI2 inhibited Ras-GAP. The stimulatory effect of PGF2 alpha was saturable and structure-specific and competed with the inhibitory effect of arachidonic acid. Arachidonic acid also inhibited the catalytic activity of NF1, but prostaglandins were not stimulatory. These results suggest a mechanism for the allosteric control of Ras function through the modulation of arachidonate metabolism. 相似文献
2.
A cytoplasmic protein inhibits the GTPase activity of H-Ras in a phospholipid-dependent manner 总被引：8，自引：0，他引：8
A cytoplasmic protein has been identified that inhibits the guanosine triphosphatase (GTPase) activity of bacterially synthesized, cellular H-Ras protein. This GTPase inhibiting protein is able to counteract the activity of GTPase activating protein (GAP), which has been postulated to function as a negative regulator of Ras activity. The potential biological importance of the GTPase inhibiting protein is further supported by its interaction with lipids. Phospholipids produced in cells as a consequence of mitogenic stimulation increase the activity of the GTPase inhibiting protein, as well as inhibit the activity of GAP. The interaction of such lipids with each of these two regulatory proteins would, therefore, tend to increase the biological activity of Ras and stimulate cell proliferation. 相似文献
3.
Inhibition of GTPase activating protein stimulation of Ras-p21 GTPase by the Krev-1 gene product 总被引：33，自引：0，他引：33
M Frech J John V Pizon P Chardin A Tavitian R Clark F McCormick A Wittinghofer 《Science (New York, N.Y.)》1990,249(4965):169-171
Krev-1 is known to suppress transformation by ras. However, the mechanism of the suppression is unclear. The protein product of Krev-1, Rap1A-p21, is identical to Ras-p21 proteins in the region where interaction with guanosine triphosphatase (GTPase) activating protein (GAP) is believed to occur. Therefore, the ability of GAP to interact with Rap1A-p21 was tested. Rap1A-p21 was not activated by GAP but bound tightly to GAP and was an effective competitive inhibitor of GAP-mediated Ras-GTPase activity. Binding of GAP to Rap1A-p21 was strictly guanosine triphosphate (GTP)-dependent. The ability of Rap1A-p21 to bind tightly to GAP may account for Krev-1 suppression of transformation by ras. This may occur by preventing interaction of GAP with Ras-p21 or with other cellular proteins necessary for GAP-mediated Ras GTPase activity. 相似文献
4.
Plexins are cell surface receptors for semaphorin molecules, and their interaction governs cell adhesion and migration in a variety of tissues. We report that the Semaphorin 4D (Sema4D) receptor Plexin-B1 directly stimulates the intrinsic guanosine triphosphatase (GTPase) activity of R-Ras, a member of the Ras superfamily of small GTP-binding proteins that has been implicated in promoting cell adhesion and neurite outgrowth. This activity required the interaction of Plexin-B1 with Rnd1, a small GTP-binding protein of the Rho family. Down-regulation of R-Ras activity by the Plexin-B1-Rnd1 complex was essential for the Sema4D-induced growth cone collapse in hippocampal neurons. Thus, Plexin-B1 mediates Sema4D-induced repulsive axon guidance signaling by acting as a GTPase activating protein for R-Ras. 相似文献
5.
Insulin rapidly increases diacylglycerol by activating de novo phosphatidic acid synthesis 总被引：10，自引：0，他引：10
R V Farese T S Konda J S Davis M L Standaert R J Pollet D R Cooper 《Science (New York, N.Y.)》1987,236(4801):586-589
The mechanisms whereby insulin increases diacylglycerol in BC3H-1 myocytes were examined. When [3H]arachidonate labeling of phospholipids was used as an indicator of phospholipase C activation, transient increases in [3H]diacylglycerol were observed between 0.5 and 10 minutes after the onset of insulin treatment. With [3H]glycerol labeling as an indicator of de novo phospholipid synthesis, [3H]diacylglycerol was increased maximally at 1 minute and remained elevated for 20 minutes. [3H]Glycerol-labeled diacylglycerol was largely derived directly from phosphatidic acid. Insulin increased de novo phosphatidic acid synthesis within 5 to 10 seconds; within 1 minute, this synthesis was 60 times greater than that of controls. Thus, the initial increase in diacylglycerol is due to both increased hydrolysis of phospholipids and a burst of de novo phosphatidic acid synthesis. After 5 to 10 minutes, de novo phosphatidic acid synthesis continues as a major source of diacylglycerol. Both phospholipid effects of insulin seem important for generating diacylglycerol and other phospholipid-derived intracellular signaling substances. 相似文献
6.
南京板鸭加工过程中肌内磷脂与游离脂肪酸含量的变化 总被引：2，自引：0，他引：2
研究了南京板鸭各个加工工艺阶段的股二头肌肌内磷脂与游离脂肪酸含量的变化.采用氯仿-甲醇溶液提取肌内脂质,采用固相萃取法将游离脂肪酸和磷脂与其他脂类分离,用高效液相色谱分析各种磷脂组分的含量,通过毛细管气相色谱分析了游离脂肪酸的含量.结果表明,在南京板鸭加工过程中,各种磷脂含量显著降低,游离脂肪酸含量显著提高,游离脂肪酸含量的提高与磷脂含量的降低与脑磷脂含量的下降关系密切. 相似文献
7.
Binding of GAP to activated PDGF receptors 总被引：93，自引：0，他引：93
The ras proto-oncogene products appear to relay intracellular signals via the Ras guanosine triphosphatase (GTPase) activator protein, GAP. In dog epithelial cells expressing human platelet-derived growth factor (PDGF) receptors, binding of PDGF caused approximately one-tenth of the total GAP molecules to complex with the receptor. Studies with mutant PDGF receptors showed that maximum association required both receptor kinase activity and phosphorylatable tyrosine residues at both the identified sites of receptor autophosphorylation. 相似文献
8.
Guanosine triphosphatase activating protein (GAP) interacts with the p21 ras effector binding domain 总被引：97，自引：0，他引：97
A cytoplasmic protein that greatly enhances the guanosine triphosphatase (GTPase) activity of N-ras protein but does not affect the activity of oncogenic ras mutants has been recently described. This protein (GAP) is shown here to be ubiquitous in higher eukaryotes and to interact with H-ras as well as with N-ras proteins. To identify the region of ras p21 with which GAP interacts, 21 H-ras mutant proteins were purified and tested for their ability to undergo stimulation of GTPase activity by GAP. Mutations in nonessential regions of H-ras p21 as well as mutations in its carboxyl-terminal domain (residues 165-185) and purine binding region (residues 117 and 119) did not decrease the ability of the protein to respond to GAP. In addition, an antibody against the carboxyl-terminal domain did not block GAP activity, supporting the conclusion that GAP does not interact with this region. Transforming mutations at positions 12, 59, and 61 (the phosphoryl binding region) abolished GTPase stimulation by GAP. Point mutations in the putative effector region of ras p21 (amino acids 35, 36, and 38) were also insensitive to GAP. However, a point mutation at position 39, shown previously not to impair effector function, did not alter GAP-p21 interaction. These results indicate that GAP interaction may be essential for ras p21 biological activity and that it may be a ras effector protein. 相似文献
9.
A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants 总被引：143，自引：0，他引：143
The role of guanine nucleotides in ras p21 function was determined by using the ability of p21 protein to induce maturation of Xenopus oocytes as a quantitative assay for biological activity. Two oncogenic mutant human N-ras p21 proteins, Asp12 and Val12, actively induced maturation, whereas normal Gly12 p21 was relatively inactive in this assay. Both mutant proteins were found to be associated with guanosine triphosphate (GTP) in vivo. In contrast, Gly12 p21 was predominantly guanosine diphosphate (GDP)-bound because of a dramatic stimulation of Gly12 p21-associated guanosine triphosphatase (GTPase) activity. A cytoplasmic protein was shown to be responsible for this increase in activity. This protein stimulated GTP hydrolysis by purified Gly12 p21 more than 200-fold in vitro, but had no effect on Asp12 or Val12 mutants. A similar factor could be detected in extracts from mammalian cells. It thus appears that, in Xenopus oocytes, this protein maintains normal p21 in a biologically inactive, GDP-bound state through its effect on GTPase activity. Furthermore, it appears that the major effect of position 12 mutations is to prevent this protein from stimulating p21 GTPase activity, thereby allowing these mutants to remain in the active GTP-bound state. 相似文献
10.
Fatty acid composition of neutral lipids （NLs）, phospholipids （PLs） and free fatty acids （FFAs） from intramuscular fat （IMF）, lipid oxidation and lipase activity in muscle Semimembranosus （SM） and msucle Biceps femoris （BF） of dry-cured Xuanwei ham during the 90-d salting stages were analysed. The salt content increased from 0.34 to 3.52%in BF and from 0.10 to 5.42%in SM during the 90 d salting stage, respectively. PLs of IMF in both BF and SM decreased 54.70%（P〈0.001） and 34.64%（P〈0.05）, furthermore, the saturated fatty acids （SFA）, monounsaturated fatty acids （MUFA） and polyunsaturated fatty acids （PUFA） of PLs in both muscles were hydrolysed almost isochronously. FFAs were increased from 0.46 g 100 g-1 lipids to 2.92 g 100 g-1 lipids in BF at the end of salting, which was lower than SM （from 1.29 g 100 g-1 lipids to 9.70 g 100 g-1 lipids）. The activities of acid lipase, neutral lipase and acid phospholipase all remained active in the 90 d. The thiobarbituric acid reactive substances （TBARS） was slowly increased to 1.34 mg kg-1 muscle in BF and to 2.44 mg kg-1 muscle in SM during the salting stage. In conclusion, the controlled salting process prompted the hydrolysis of PLs of IMF notably and increased the lipid oxidation of muscles within some limits. 相似文献
11.
血液和组织标本中脂肪酸组成的毛细管柱气相色谱分析 总被引：3，自引：0，他引：3
用氯仿甲醇抽提、三氟化硼－乙醚甲醇酯化，然后利用毛细管柱和程序升温的方法进行气相色谱分析，建立了血浆和红细胞膜总脂以及组织磷脂和中性脂脂肪酸组成的毛细管柱气相色谱分析法。图谱表明各峰间分离效果良好、峰形尖锐、干扰少。各种脂肪酸的最小检测限均可达１０－（－１１）ｇ／ｓ，ＦＩＤ对各脂肪酸的响应均呈线性。实验重复性好，回收率达定量分析要求． 相似文献
12.
B Samuelsson S E Dahlén J A Lindgren C A Rouzer C N Serhan 《Science (New York, N.Y.)》1987,237(4819):1171-1176
Arachidonic acid is released from membrane phospholipids upon cell stimulation (for example, by immune complexes and calcium ionophores) and converted to leukotrienes by a 5-lipoxygenase that also has leukotriene A4 synthetase activity. Leukotriene A4, an unstable epoxide, is hydrolyzed to leukotriene B4 or conjugated with glutathione to yield leukotriene C4 and its metabolites, leukotriene D4 and leukotriene E4. The leukotrienes participate in host defense reactions and pathophysiological conditions such as immediate hypersensitivity and inflammation. Recent studies also suggest a neuroendocrine role for leukotriene C4 in luteinizing hormone secretion. Lipoxins are formed by the action of 5- and 15-lipoxygenases on arachidonic acid. Lipoxin A causes contraction of guinea pig lung strips and dilation of the microvasculature. Both lipoxin A and B inhibit natural killer cell cytotoxicity. Thus, the multiple interaction of lipoxygenases generates compounds that can regulate specific cellular responses of importance in inflammation and immunity. 相似文献
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14.
Activation of the cellular proto-oncogene product p21Ras by addition of a myristylation signal 总被引：30，自引：0，他引：30
J E Buss P A Solski J P Schaeffer M J MacDonald C J Der 《Science (New York, N.Y.)》1989,243(4898):1600-1603
The 21-kD proteins encoded by ras oncogenes (p21Ras) are modified covalently by a palmitate attached to a cysteine residue near the carboxyl terminus. Changing cysteine at position 186 to serine in oncogenic forms produces a nonpalmitylated protein that fails to associate with membranes and does not transform NIH 3T3 cells. Nonpalmitylated p21Ras derivatives were constructed that contained myristic acid at their amino termini to determine if a different form of lipid modification could restore either membrane association or transforming activity. An activated p21Ras, altered in this way, exhibited both efficient membrane association and full transforming activity. Surprisingly, myristylated forms of normal cellular Ras were also transforming. This demonstrates that Ras must bind to membranes in order to transmit a signal for transformation, but that either myristate or palmitate can perform this role. However, the normal function of cellular Ras is diverted to transformation by myristate and therefore must be regulated ordinarily by some unique property of palmitate that myristate does not mimic. Myristylation thus represents a novel mechanism by which Ras can become transforming. 相似文献
15.
为探究即食虾干加工过程中脂质的变化情况，以凡纳滨对虾为研究对象，分别取鲜虾、煮后、干燥2 h、干燥4 h的样品，对总脂含量、脂质组成、脂肪酸组成、酸价（Acid value, AV）、过氧化值（Peroxide value, POV）、硫代巴比妥酸反应值（Thiobarbituric acid reactive substances, TBARS）进行了检测分析。结果表明，鲜虾总脂含量为8.74 g/100 g（干基计），在煮制和干制过程中变化不显著（P>0.05）。脂质组成发生明显变化，煮后甘油三酯和游离脂肪酸的比例显著降低（P＜0.05），而磷脂比例显著升高（P＜0.05）。在干制过程，磷脂比例呈下降趋势，游离脂肪酸比例呈上升的趋势，而胆固醇比例相对稳定。脂肪酸组成在加工过程总体变化较小，其中多不饱和脂肪酸在干制阶段含量有所减少，相对的提高了饱和脂肪酸含量。虾干加工过程中，POV呈先上升后下降的变化趋势，AV在煮后急剧下降，而干制后增加，TBARS一直上升。由此，虾干加工过程中煮制和热风干燥会影响脂质组分的比例，同时引起脂质的氧化分解。本研究为即食虾干加工工艺的优化、品质控制及风味形成提供了理论参考。 相似文献
16.
Inhibition of serum- and ras-stimulated DNA synthesis by antibodies to phospholipase C 总被引：17，自引：0，他引：17
Several immunologically distinct isozymes of inositol phospholipid-specific phospholipase C (PLC) have been purified from bovine brain. Murine NIH 3T3 fibroblasts were found to express PLC-gamma, but the expression of PLC-beta was barely detectable by radioimmunoassay or protein immunoblot. A mixture of monoclonal antibodies was identified that neutralizes the biological activity of both endogenous and injected purified PLC-gamma. When co-injected with oncogenic Ras protein or PLC-gamma, this mixture of antibodies inhibited the induction of DNA synthesis that characteristically results from the injection of these proteins into quiescent 3T3 cells. However, when oncogenic Ras protein or PLC-gamma was co-injected with a neutralizing monoclonal antibody to Ras, only the DNA synthesis induced by the Ras protein was inhibited--that induced by PLC was unaffected. These results suggest that the Ras protein is an upstream effector of PLC activity in phosphoinositide-specific signal transduction and that PLC-gamma activity is necessary for Ras-mediated induction of DNA synthesis. 相似文献
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19.
Nelson CD Perry SJ Regier DS Prescott SM Topham MK Lefkowitz RJ 《Science (New York, N.Y.)》2007,315(5812):663-666
Seven-transmembrane receptor (7TMR) signaling is transduced by second messengers such as diacylglycerol (DAG) generated in response to the heterotrimeric guanine nucleotide-binding protein Gq and is terminated by receptor desensitization and degradation of the second messengers. We show that beta-arrestins coordinate both processes for the Gq-coupled M1 muscarinic receptor. beta-Arrestins physically interact with diacylglycerol kinases (DGKs), enzymes that degrade DAG. Moreover, beta-arrestins are essential for conversion of DAG to phosphatidic acid after agonist stimulation, and this activity requires recruitment of the beta-arrestin-DGK complex to activated 7TMRs. The dual function of beta-arrestins, limiting production of diacylglycerol (by receptor desensitization) while enhancing its rate of degradation, is analogous to their ability to recruit adenosine 3',5'-monophosphate phosphodiesterases to Gs-coupled beta2-adrenergic receptors. Thus, beta-arrestins can serve similar regulatory functions for disparate classes of 7TMRs through structurally dissimilar enzymes that degrade chemically distinct second messengers. 相似文献
20.
The mammalian target of rapamycin, mTOR, is a central regulator of cell growth. Its activity is regulated by Rheb, a Ras-like small guanosine triphosphatase (GTPase), in response to growth factor stimulation and nutrient availability. We show that Rheb regulates mTOR through FKBP38, a member of the FK506-binding protein (FKBP) family that is structurally related to FKBP12. FKBP38 binds to mTOR and inhibits its activity in a manner similar to that of the FKBP12-rapamycin complex. Rheb interacts directly with FKBP38 and prevents its association with mTOR in a guanosine 5'-triphosphate (GTP)-dependent manner. Our findings suggest that FKBP38 is an endogenous inhibitor of mTOR, whose inhibitory activity is antagonized by Rheb in response to growth factor stimulation and nutrient availability. 相似文献