Inhibition by cAMP of Ras-Dependent Activation of Raf

Cook, Simon J.; McCormick, Frank

doi:10.1126/science.7694367

Cited by 911 publications

(636 citation statements)

References 38 publications

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“…Although 5 735 could be phosphorylated by protein kinase A, the physiological significance of the phosphorylation of RID is not known. In contrast, the phosphorylation of Raf-I by protein kinase A reduced its binding to ras p21 [33,34]. The decrease of the affinity of Raf-1 for ras p21 by protein kinase A might be one of the mechanism by which the signals through cyclic AMP inhibit the proliferation of the cells [35].…”

Section: Discussionmentioning

confidence: 98%

“…the interaction ofras p21 and rapl p21 with RID It has been known that Raf-1 is phosphorylated by protein kinase A and that phosphorylation of Raf-1 reduces the binding of Raf-1 to ras p21 [33,34]. Therefore, we examined whether protein kinase A affects the interaction of RGL with ras p21 and rapl p21.…”

Section: Effect Of the Phosphorylation Of Rid By Protein Kinase A Onmentioning

confidence: 99%

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rap1 p21 regulates the interaction of ras p21 with RGL, a new effector protein of ras p21

et al. 1995

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We have recently found that ralGDS family members (RGL and ralGDS) are putative effector proteins of ras p21. rapl p21 is a small GTP-binding protein which has the same amino acid sequence as the effector loop of ras p21. We examined the effect of rapl p21 on the interaction of ras p21 with RGL. The GTP-bound form of rapl p21 interacted with RGL as well as did ras p21. rapl p21 inhibited the interaction of ras p21 with RGL. RGL was phosphorylated by cyclic AMP-dependent protein kinase (protein kinase A). Phosphorylation of RGL did not affect its binding to ras p21 and rapl p21 under the conditions that phosphorylation of Raf-1 reduced its affinity for ras p21. These results demonstrate that rapl p21 but not protein kinase A regulates the interaction of ras p21 with RGL and suggest that rapl p21 and protein kinase A may cooperate to distinguish the signal of ras p21 to RGL from that to Raf-1.

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Section: Discussionmentioning

confidence: 98%

Section: Effect Of the Phosphorylation Of Rid By Protein Kinase A Onmentioning

confidence: 99%

rap1 p21 regulates the interaction of ras p21 with RGL, a new effector protein of ras p21

et al. 1995

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“…In addition, cAMP also inhibits insulin and growth-factor-stimulated MAPK signalling in most cell types [25,[37][38][39][40], with the exception of Swiss 3T3 and PC12 cells (reviewed in [25]). Our previous studies have shown that SpcAMP counter-regulates insulin's effect on PP-2A inactivation by decreasing the tyrosine phosphorylation of PP-2A and restoring its catalytic activity [25].…”

Section: Discussionmentioning

confidence: 99%

Role of Janus kinase-2 in insulin-mediated phosphorylation and inactivation of protein phosphatase-2A and its impact on upstream insulin signalling components

Begum

Ragolia

1999

Biochemical Journal

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Our recent studies indicate that insulin rapidly inactivates serine/threonine protein phosphatase-2A (PP-2A) by increasing tyrosine phosphorylation on the catalytic subunit. The exact mechanism of PP-2A inactivation by insulin in vivo is unclear. The Janus kinase (JAK) family of non-receptor protein tyrosine kinases constitute a novel type of signal-transduction pathway which is activated in response to a wide variety of polypeptide ligands, including insulin. In this study we investigated the potential role of JAK-2 in insulin-mediated tyrosine phosphorylation and inactivation of PP-2A using the rat skeletal muscle cell line L6. Co-immunoprecipitation studies revealed that PP-2A is associated with JAK-2 in the basal state. Insulin treatment did not alter JAK-2 association with PP-2A, but did increase JAK-2-mediated tyrosine phosphorylation of the PP-2A catalytic subunit and therefore inhibited PP-2A enzymic activity. Furthermore, PP-2A is associated with phosphoinositide 3-kinase (PI-3K) in the basal state and insulin treatment increases the catalytic activity of PI-3K bound to PP-2A. Pretreatment with AG-490, a specific JAK-2 inhibitor, and SpcAMP, a cAMP agonist, prevented the insulin-mediated increase in (i) JAK-2 kinase activity, (ii) PP-2A tyrosine phosphorylation, (iii) PP-2A inactivation and restored the enzyme activity to control levels, and (iv) PP-2A and JAK-2-associated PI-3K activity. These observations, together with the fact that insulin rapidly activates JAK-2 in L6 cells, and that this is accompanied by an increase in tyrosine phosphorylation of PP-2A in JAK-2 immunoprecipitates, suggest that insulin controls the activation status of PP-2A by tyrosine phosphorylation via JAK-2. PP-2A inactivation may result in an amplification of insulin-generated signals at the level of PI-3K.

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“…Negative regulation of Raf has been observed previously both at the level of activation and with active Raf. Phosphorylation of c-Raf-1 on Ser-43 of the regulatory domain trough PKA inhibits the Ras dependent activation of Raf-1 kinase leading to the downregulation of the classic cascade and to inhibition of growth factor induced cell proliferation of Ratla and NIH 3T3 cells [12,29,30]. Inactivation of constitutively active c-Raf-1 was observed in Jurkat T-cells [31].…”

Section: Discussionmentioning

confidence: 99%

Differential regulation of Raf isozymes by growth versus differentiation inducing factors in PC12 pheochromocytoma cells

et al. 1996

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PC12 pheochromocytoma cells possess four known MEK activators: A-, B-, c-Raf-I and MEKK. In order to examine whether differentiation factors or growth factors have a Raf isozyme preference for activation of the mitogenic cytoplasmic Raf-MEK-MAPK protein kinase cascade, the activation kinetics of these enzymes in response to epidermal growth factor (EGF) and nerve growth factor (NGF) were compared. An initial activation of all three Raf kinases was noticed, but only A-and B-Raf showed sustained activation by NGF, which was not seen after EGF treatment. Furthermore, expression of oncogenic versions of all three Raf kinases as weil~ as a potentially Rafindependent MEK activator, v-Mos, leads to activation of MAPK and to differentiation of PC12 cells. These data suggest a differential regulation of Raf kinases and that probably no alternative Raf substrates are involved in differentiation processes of PC12 cells.

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Inhibition by cAMP of Ras-Dependent Activation of Raf

Cited by 911 publications

References 38 publications

rap1 p21 regulates the interaction of ras p21 with RGL, a new effector protein of ras p21

rap1 p21 regulates the interaction of ras p21 with RGL, a new effector protein of ras p21

Role of Janus kinase-2 in insulin-mediated phosphorylation and inactivation of protein phosphatase-2A and its impact on upstream insulin signalling components

Differential regulation of Raf isozymes by growth versus differentiation inducing factors in PC12 pheochromocytoma cells

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