Desensitization of the Ca2+-mobilizing system to serum growth factors by Ha-ras and v-mos.

Maly, Karl; Doppler, Wolfgang; Oberhuber, Hermann; Meusburger, Hugo; Hofmann, Johann; Jaggi, Rolf; Grunicke, H.

doi:10.1128/mcb.8.10.4212

Cited by 25 publications

(15 citation statements)

References 22 publications

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“…These saturation levels remained practically unchanged until at least 40 min after the start of exposure to the agonists. On the basis of these observations and those of others (20,27,31), 30 min was chosen as the time after stimulation when the diverse cell lines were compared in terms of IP production. Given the variety of cell lines studied and the multiple pathways and enzymes involved in production and interconversion of IP metabolites (8) [3H]bradykinin binding.…”

Section: Methodsmentioning

confidence: 99%

“…Initial reports suggested that ras proteins could act as positive or negative regulatory G proteins of phospholipase C (PLC) or phospholipase A2 (PLA2) (4,7,15,27,33,34). However, recent reports studying the phosphoinositide pathway in cells transformed by ras and other oncogenes (1,6,20,31) or in normal cells microinjected with neutralizing ras antibodies (36) clearly indicate that ras proteins are not direct regulatory elements of either PLC or PLA2. We and others showed, for example, that transformation by ras resulted in specific uncoupling of PLC from external agonists including platelet-derived growth factor (PDGF) bombesin, serum, and a-thrombin (1,6,7,20,27,31).…”

mentioning

confidence: 97%

“…Ours and other studies (1,6,20,27,31) showed previously that the uncoupling between PLC and external signals (PDGF, bombesin, and thrombin) was not the result of alteration of either the functionality or the number of the specific receptors or of the basal activity of PLC. Since the specific receptors and the effector PLC enzyme appeared not to be affected, we tried to determine here whether alterations occurred at the G-protein level.…”

mentioning

confidence: 99%

“…Initial reports suggested that ras proteins could act as positive or negative regulatory G proteins of phospholipase C (PLC) or phospholipase A2 (PLA2) (4,7,15,27,33,34). However, recent reports studying the phosphoinositide pathway in cells transformed by ras and other oncogenes (1,6,20,31) 6,7,20,27,31). Interestingly, however, the same changes were observed in cells transformed by membrane-associated (src, trk, met) and cytoplasmic (mos, raf) oncogenes but not nuclear oncogenes (myc, fos) (1).…”

mentioning

confidence: 99%

“…However, recent reports studying the phosphoinositide pathway in cells transformed by ras and other oncogenes (1,6,20,31) or in normal cells microinjected with neutralizing ras antibodies (36) clearly indicate that ras proteins are not direct regulatory elements of either PLC or PLA2. We and others showed, for example, that transformation by ras resulted in specific uncoupling of PLC from external agonists including platelet-derived growth factor (PDGF) bombesin, serum, and a-thrombin (1,6,7,20,27,31). Interestingly, however, the same changes were observed in cells transformed by membrane-associated (src, trk, met) and cytoplasmic (mos, raf) oncogenes but not nuclear oncogenes (myc, fos) (1).…”

mentioning

confidence: 99%

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Alterations of G-protein coupling function in phosphoinositide signaling pathways of cells transformed by ras and other membrane-associated and cytoplasmic oncogenes.

Alonso¹,

Srivastava²,

Santos³

1990

Mol. Cell. Biol.

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We showed previously that transformation by cytoplasmic and membrane-associated oncogenes including ras results in uncoupling between surface stimulation by platelet-derived growth factor, bombesin, and serum and activation of intracellular phospholipase C (PLC); this uncoupling does not involve alterations at the receptor or effector enzyme levels (T. Alonso, R. 0. Morgan, J. C. Marvizon, H. Zarbl, and E. Santos, Proc. Natl. Acad. Sci. USA 85:4271-4275, 1988). In this study, we stimulated normal and oncogene-transformed NIH 3T3 cells with fluoroaluminate (AMF4 ), thus directly activating PLC-associated G protein(s) and bypassing the receptor step. AlF4 -elicited PLC responses were significantly impaired in transformed cells when compared with those in their normal counterparts, suggesting that the uncoupling of PLC is the result, at least in part, of functional impairment at the G-protein level. Transformation by ras oncogenes has also been reported to result in enhanced PLC response to bradykinin resulting from increased receptor numbers (G. Parries, R. Hoebel, and E. Racker, Proc. Natl. Acad. Sci. USA 84:2648-2652, 1987; J. Downward, J. de Gunzburg, R. Riehl, and R. Weinberg, Proc. Natl. Acad. Sci. USA 85: [5774][5775][5776][5777][5778] 1988). We demonstrate here that transformation by other membrane-associated and cytoplasmic oncogenes also results in increased responsiveness to bradykinin ("supercoupling") and enhanced receptor numbers. However, there is no direct correlation between the number of receptors and the enhancement in responsiveness, suggesting that other factors besides receptor number are also involved in the enhanced responses. We propose that a common effect of transformation by cytoplasmic and membrane-associated oncogenes is functional alteration of coupling G proteins and that a similar modification of different kinds of G proteins may account for the pleiotropic alterations of signal transduction (uncoupling and supercoupling) observed.Mammalian ras genes belong to a multigene family encoding closely related proteins designated p21 ras. Despite considerable knowledge about the structural and functional aspects of the ras proteins, their functional role in physiological and pathological processes still remains obscure (3, 30). The cellular location, as well as the structural and biochemical similarities to G proteins, suggests that ras proteins, in some as yet undetermined manner, participate in the transduction of cellular signals.A direct relation of ras proteins and the adenylate cyclase pathway of vertebrates has been discounted (5, 9), and recently, studies have focused on a possible role of ras proteins in the phosphoinositide signaling pathway that generates second messengers such as inositol trisphosphate (UP3) and diacylglycerol. Initial reports suggested that ras proteins could act as positive or negative regulatory G proteins of phospholipase C (PLC) or phospholipase A2 (PLA2) (4,7,15,27,33,34). However, recent reports studying the phosphoinositide pathway in cells transformed ...

show abstract

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 97%

mentioning

confidence: 99%

“…Initial reports suggested that ras proteins could act as positive or negative regulatory G proteins of phospholipase C (PLC) or phospholipase A2 (PLA2) (4,7,15,27,33,34). However, recent reports studying the phosphoinositide pathway in cells transformed by ras and other oncogenes (1,6,20,31) 6,7,20,27,31). Interestingly, however, the same changes were observed in cells transformed by membrane-associated (src, trk, met) and cytoplasmic (mos, raf) oncogenes but not nuclear oncogenes (myc, fos) (1).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

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Alterations of G-protein coupling function in phosphoinositide signaling pathways of cells transformed by ras and other membrane-associated and cytoplasmic oncogenes.

Alonso¹,

Srivastava²,

Santos³

1990

Mol. Cell. Biol.

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Cytokinesis is more rapid in Ha‐T24‐ras transfected rat embryo fibroblasts than in non‐transfected control cells

Boylan

Zimmer

et al. 1992

Cell Motil. Cytoskeleton

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It has long been known that neoplastic cells are characterized by increases in cell motility. Earlier studies from this laboratory indicated that mitotic events were also altered in many tumor and experimentally transformed cells and that this included increases in metaphase duration and a reduction in the duration of cytokinesis. The studies presented in this paper were done to determine whether or not transfection of normal rat embryo fibroblasts by the Ha-T24-ras oncogene could also produce such alterations in mitotic events. The results obtained with the use of time lapse video microscopy indicate that neither the duration of metaphase nor the rate of chromosome movement during anaphase was altered but that the rate of furrow progression during cytokinesis occurred at a significantly more rapid rate. Thus, the cellular alterations induced by transfection with Ha-T24-ras accelerate microfilament-dependent cytokinetic furrowing without significant effects on microtubule-dependent mitotic events. One of several possible mechanisms that could account for these observations involves a down regulation of protein kinase C which has been reported to occur in many neoplastic cells including those transformed by ras. Such a hypothesis could also have broader implications because it may be applicable to the increase in motility and metastatic activity generally observed in transformed cells.

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Transforming potentials of epidermal growth factor and nerve growth factor receptors inversely correlate with their phospholipase C gamma affinity and signal activation.

et al. 1996

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The exchange of nerve growth factor receptor/Trk and epidermal growth factor receptor (EGFR) phospholipase C gamma (PLC gamma) binding sites resulted in the transfer of their distinct affinities for this Src homology 2 domain‐containing protein. Relative to wild‐type EGFR, the PLC gamma affinity increase of the EGFR switch mutant EGFR.X enhanced its inositol trisphosphate (IP3) and calcium signals and resulted in a more sustained mitogen‐activated protein (MAP) kinase activation and accelerated receptor dephosphorylation. In parallel, EGFR.X exhibited a significantly decreased mitogenic and transforming potential in NIH 3T3 cells. Conversely, the transfer of the EGFR PLC gamma binding site into the Trk cytoplasmic domain context impaired the IP3/calcium signal and attenuated the MAP kinase activation and receptor dephosphorylation, but resulted in an enhancement of the ETR.X exchange mutant mitogenic and oncogenic capacity. Our findings establish the significance of PLC gamma affinity for signal definition, the role of this receptor tyrosine kinase substrate as a negative feedback regulator and the importance of this regulatory function for mitogenesis and its disturbance in oncogenic aberrations.

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Desensitization of the Ca2+-mobilizing system to serum growth factors by Ha-ras and v-mos.

Cited by 25 publications

References 22 publications

Alterations of G-protein coupling function in phosphoinositide signaling pathways of cells transformed by ras and other membrane-associated and cytoplasmic oncogenes.

Alterations of G-protein coupling function in phosphoinositide signaling pathways of cells transformed by ras and other membrane-associated and cytoplasmic oncogenes.

Cytokinesis is more rapid in Ha‐T24‐ras transfected rat embryo fibroblasts than in non‐transfected control cells

Transforming potentials of epidermal growth factor and nerve growth factor receptors inversely correlate with their phospholipase C gamma affinity and signal activation.

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