Stimulation of Membrane Ruffling and MAP Kinase Activation by Distinct Effectors of RAS

Joneson, Tom; White, Michael A.; Wigler, Michael; Bar–Sagi, Dafna

doi:10.1126/science.271.5250.810

Cited by 376 publications

(347 citation statements)

References 16 publications

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“…In contrast, RasC40 failed to stimulate cell cycle progression in REF52 ®broblasts (Joneson et al, 1996) or WT19 myeloid cells (Matsuguchi and Kraft, 1998), suggesting that its mitogenic e ects are cell type-dependent. In thyroid cells, the growth stimulatory e ects of RasC40 were reproduced by expression of p110-CAAX (Cass et al, 1999), a membrane-localized, constitutively active form of p110 .…”

Section: Discussionmentioning

confidence: 99%

Ras signaling through PI3K confers hormone-independent proliferation that is compatible with differentiation

Cass

Meinkoth

2000

Oncogene

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Hormones are specialized mitogens that stimulate proliferation in their di erentiated target cells. Thyrotropin (TSH), the physiologic regulator of thyroid cells, stimulates cAMP-mediated proliferation and thyroidspeci®c gene expression. The mitogenic e ects of TSH require Ras, therefore Ras activation should be compatible with the maintenance of thyroid di erentiation. However, expression of activated Ras extinguishes the di erentiated phenotype of thyroid cells. One explanation for this apparent paradox is the selective utilization of Ras e ector pathways. We tested the hypothesis that Ras signaling through PI3K mediates the mitogenic e ects of TSH in cells which retain their di erentiated character. Expression of a Ras e ector mutant (RasV12S35) that signals preferentially through Raf-1, although su cient to confer TSH-independent proliferation, abolished hormone-regulated expression of thyroglobulin and the sodium/iodide symporter. In contrast, expression of a Ras mutant (RasV12C40) that binds selectively to PI3K conferred TSH-independent proliferation without marked e ects on thyroid-speci®c gene expression. Unlike the inhibitory e ects of TSH on the proliferation of RasV12S35-expressing cells, TSH enhanced RasV12C40-stimulated proliferation by further increasing the activity of p70s6k, an important mediator of the mitogenic e ects of TSH and RasV12C40. These results demonstrate that channeling Ras-dependent signals to PI3K confers TSH with the ability to stimulate proliferation in di erentiated cells. Oncogene (2000) 19, 924 ± 932.

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Section: Discussionmentioning

confidence: 99%

Ras signaling through PI3K confers hormone-independent proliferation that is compatible with differentiation

Cass

Meinkoth

2000

Oncogene

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“…RalGDS can serve as an exchange factor and activator of the Ras-related proteins RalA and RalB. Ras(12V/40C) can still promote membrane ru ing, activate the JNK pathway (White et al, 1995;Khosravi-Far et al, 1996;Joneson et al, 1996), and may mediate transformation by activation of PI3K (Joneson et al, 1996;Rodriguez-Viciana et al, 1997). To de®ne the Raf-independent pathways that facilitate Ras transformation of RIE-1 cells, it will be important to determine whether constitutive activation of Ral proteins or PI3K alone can cause transformation of RIE-1 cells.…”

Section: Discussionmentioning

confidence: 99%

“…However, it should be emphasized that the value of this and other e ector mutants is based on what they don't bind, since what they do bind remains unresolved until we have a complete knowledge of all relevant Ras e ectors. Thus, since Ras(12V/35S) binds Raf, as well as RalGDS, RGL, and p120 GAP (White et al, 1995;Khosravi-Far et al, 1996;Joneson et al, 1996), it can still activate both Raf-dependent and Raf-independent pathways. In contrast, this mutant (and the 37G mutant) is impaired in its ability to activate PI3K (RodriguezViciana et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…H-Ras (12V/37G) may cause transformation, in part, through interaction with RalGDS , whereas H-Ras(12V/40C) transforming activity has been attributed to activation of PI3K (Joneson et al, 1996;Rodriguez-Viciana et al, 1997). Although HRas(12V/35S) retains the ability to interact with Raf and RalGDS, it is impaired in its interaction with other candidate Ras e ectors (White et al, 1995;KhosraviFar et al, 1996).…”

Section: Farnesyltransferase Inhibitors Impair Ras- But Not Src- Trmentioning

confidence: 99%

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Ras, but not Src, transformation of RIE-1 epithelial cells is dependent on activation of the mitogen-activated protein kinase cascade

et al. 1998

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Src transformation of NIH3T3 mouse ®broblasts has been shown to be dependent on Ras function. Since we recently showed that the signaling pathways that mediate Ras transformation of RIE-1 rat intestinal epithelial cells are distinct from those that cause Ras transformation of ®broblasts, we utilized three approaches to determine if Src transformation of RIE-1 cells is dependent on Ras. First, although both Ras and Src cause upregulation of an epidermal growth factor (EGF) receptor-dependent autocrine growth loop, only Ras transformation required this activity. Second, whereas both Src and Ras caused upregulation of the p42 and p44 mitogen-activated protein kinases (MAPKs), only Ras transformation was blocked by the inhibition of MAPK activation by treatment with the PD 98059 MEK inhibitor. Third, treatment with the farnesyltransferase inhibitor FTI-277 blocked Ras, but not Src, transformation. Taken together, these observations suggest that Src transformation of RIE-1 cells is not dependent on Ras. Finally, we determined that Ras activation of Raf-independent pathways alone is su cient to cause growth transformation of RIE-1 cells. Thus, both Ras and Src cause transformation of RIE-1 cells via pathways distinct from those required to cause transformation of NIH3T3 cells.

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“…Activating mutations of Ras have an impaired intrinsic GTPase activity and are insensitive to GTPaseactivating proteins (GAPs), resulting in constitutive signaling to downstream targets. Genetic and biochemical studies have revealed that Ras, in its active GTPbound form, can interact with multiple distinct e ectors, inducing at least two distinct pathways that are necessary for its transformation ability, and act synergistically to induce malignant transformation (Joneson and Bar-Sagi, 1997;Joneson et al, 1996;Khosravi-Far et al, 1996;Marshall, 1996).…”

Section: Introductionmentioning

confidence: 99%

Concomitant activation of MEK-1 and Rac-1 increases the proliferative potential of thyroid epithelial cells, without affecting their differentiation

1998

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Activating point mutations in the Ras oncogene occur in a large number of human tumors, especially of epithelial origin. In thyroid follicular cells, ectopic expression of oncogenic H-Ras results in growth factor-independent proliferation, loss of di erentiation and tumor formation in nude mice. In ®broblasts concomitant activation of the MAP kinase cascade and the small GTPase Rac-1 leads to full malignant transformation. We have tested the e ects of these key downstream mediators of Ras in thyroid epithelial cells, by stably expressing either a constitutively active form of MEK-1 (MEK DN3/S218E/S222D ), a constitutively active form of Rac-1 (Val12-Rac), or both. While the activation of one molecule or the other results in a weak phenotype, concomitant activation of both MEK-1 and Rac-1 in thyroid cells leads to growth factor-independent proliferation, morphological transformation and anchorage-independent growth. However, in contrast to Ras-transformed thyroid cells, the ones expressing the constitutively active forms of MEK-1 and Rac-1 maintain their di erentiate phenotype and fail to form tumors when injected into nude mice. Thus, in thyroid epithelial cells, concomitant activation of MEK-1 and Rac-1 can reproduce only a subset of the Rasinduced e ects and is not su cient to cause full malignant transformation. Signi®cantly, Ras-mediated increased proliferation and loss of di erentiation can be dissociated in these cells.

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Stimulation of Membrane Ruffling and MAP Kinase Activation by Distinct Effectors of RAS

Cited by 376 publications

References 16 publications

Ras signaling through PI3K confers hormone-independent proliferation that is compatible with differentiation

Ras signaling through PI3K confers hormone-independent proliferation that is compatible with differentiation

Ras, but not Src, transformation of RIE-1 epithelial cells is dependent on activation of the mitogen-activated protein kinase cascade

Concomitant activation of MEK-1 and Rac-1 increases the proliferative potential of thyroid epithelial cells, without affecting their differentiation

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