RAS and RHO Families of GTPases Directly Regulate Distinct Phosphoinositide 3-Kinase Isoforms

Fritsch, Ralph; Krijger, Inge de; Fritsch, Kornelia; George, Roger; Reason, Beth; Kumar, Madhu; Diefenbacher, Markus E.; Stamp, Gordon; Downward, Julian

doi:10.1016/j.cell.2013.04.031

Cited by 259 publications

(286 citation statements)

References 50 publications

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“…As pharmacologic agents can have nonspecific effects, future studies using genetic approaches such as dominant negative Rac1 mutants will be helpful to strengthen our conclusion. This observation expands on the role of Rac1 in activating the PI3K pathway as documented recently (29)(30)(31). Additionally, as a well-known modulator of growth signaling, the increase in IGF2 expression in PREX2 mutants is also expected to contribute to the activation of the PI3K/Akt pathway.…”

Section: Discussionmentioning

confidence: 80%

“…We hypothesized that the increased GEF activity of PREX2 mutants and resulting activation of Rac1 contributes to this activation of Akt based on several reports that have shown Rac1 can activate PI3K/Akt signaling by directly binding to PI3K (29)(30)(31). To test this hypothesis in our model system, we expressed a constitutively active Rac1 construct, Q61L, in primary melanocytes.…”

Section: Prex2 Mutant Tumors Have Markedly Increased Cell Proliferationmentioning

confidence: 99%

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Truncating PREX2 mutations activate its GEF activity and alter gene expression regulation in NRAS-mutant melanoma

Deribe

Shi

Rai

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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PREX2 (phosphatidylinositol-3,4,5-triphosphate-dependent Rac-exchange factor 2) is a PTEN (phosphatase and tensin homolog deleted on chromosome 10) binding protein that is significantly mutated in cutaneous melanoma and pancreatic ductal adenocarcinoma. Here, genetic and biochemical analyses were conducted to elucidate the nature and mechanistic basis of PREX2 mutation in melanoma development. By generating an inducible transgenic mouse model we showed an oncogenic role for a truncating PREX2 mutation (PREX2E824*) in vivo in the context of mutant NRAS. Using integrative cross-species gene expression analysis, we identified deregulated cell cycle and cytoskeleton organization as significantly perturbed biological pathways in PREX2 mutant tumors. Mechanistically, truncation of PREX2 activated its Rac1 guanine nucleotide exchange factor activity, abolished binding to PTEN and activated the PI3K (phosphatidyl inositol 3 kinase)/Akt signaling pathway. We further showed that PREX2 truncating mutations or PTEN deletion induces down-regulation of the tumor suppressor and cell cycle regulator CDKN1C (also known as p57KIP2). This down-regulation occurs, at least partially, through DNA hypomethylation of a differentially methylated region in chromosome 11 that is a known regulatory region for expression of the CDKN1C gene. Together, these findings identify PREX2 as a mediator of NRAS-mutant melanoma development that acts through the PI3K/PTEN/Akt pathway to regulate gene expression of a cell cycle regulator.

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Section: Discussionmentioning

confidence: 80%

Section: Prex2 Mutant Tumors Have Markedly Increased Cell Proliferationmentioning

confidence: 99%

Truncating PREX2 mutations activate its GEF activity and alter gene expression regulation in NRAS-mutant melanoma

Deribe

Shi

Rai

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Finally it is possible that there exists a direct molecular mechanism linking p110β to Pten. In any case, an activated allele of Kras would be expected to directly engage p110α (18)(19)(20)41) providing a new "accelerating" signal in the PK tumors.…”

Section: Discussionmentioning

confidence: 99%

“…For example, Kras-and Hras-dependent lung and skin tumors have been shown to rely on p110α (18,19), and this isoform has been reported to directly bind Kras. In contrast, p110β does not directly bind Ras proteins (20). In addition, loss-of-function mutations in the tumor suppressor PTEN are common in many human tumors and result in PI3K pathway activation (7).…”

mentioning

confidence: 99%

PI3K isoform dependence of PTEN-deficient tumors can be altered by the genetic context

Schmit

Utermark

Zhang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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There has been increasing interest in the use of isoform-selective inhibitors of phosphatidylinositide-3-kinase (PI3K) in cancer therapy. Using conditional deletion of the p110 catalytic isoforms of PI3K to predict sensitivity of cancer types to such inhibitors, we and others have demonstrated that tumors deficient of the phosphatase and tensin homolog (PTEN) are often dependent on the p110β isoform of PI3K. Because human cancers usually arise due to multiple genetic events, determining whether other genetic alterations might alter the p110 isoform requirements of PTEN-null tumors becomes a critical question. To investigate further the roles of p110 isoforms in PTEN-deficient tumors, we used a mouse model of ovarian endometrioid adenocarcinoma driven by concomitant activation of the rat sarcoma protein Kras, which is known to activate p110α, and loss of PTEN. In this model, ablation of p110β had no effect on tumor growth, whereas p110α ablation blocked tumor formation. Because ablation of PTEN alone is often p110β dependent, we wondered if the same held true in the ovary. Because PTEN loss alone in the ovary did not result in tumor formation, we tested PI3K isoform dependence in ovarian surface epithelium (OSE) cells deficient in both PTEN and p53. These cells were indeed p110β dependent, whereas OSEs expressing activated Kras with or without PTEN loss were p110α dependent. Furthermore, isoform-selective inhibitors showed a similar pattern of the isoform dependence in established Kras G12D /PTEN-deficient tumors. Taken together, our data suggest that, whereas in some tissues PTEN-null tumors appear to inherently depend on p110β, the p110 isoform reliance of PTEN-deficient tumors may be altered by concurrent mutations that activate p110α.ovarian cancer | PI3K inhibitors | genetically engineered mouse model

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“…This highlights the dependence of the protective role of Elmo1 and Dock180 in ECs on PI3K and AKT function. We further aimed to address the question, if the activation of AKT by Elmo1 and Dock180 is mediated by Rac1 signaling, as AKT has recently been described acting downstream of Rac1 (48,50). To this end, Rac1 activity was determined by Rac1 pull-down assays in ECs which showed a strong increase in Rac1 activation when Elmo1 and Dock180 protein levels were enhanced (Fig.…”

Section: Elmo1 and Dock180 Maintain Survival Of Ecs Via The Rac1/ Aktmentioning

confidence: 99%

The Bipartite Rac1 Guanine Nucleotide Exchange Factor Engulfment and Cell Motility 1/Dedicator of Cytokinesis 180 (Elmo1/Dock180) Protects Endothelial Cells from Apoptosis in Blood Vessel Development

Schäker

Bartsch

Patry

et al. 2015

Journal of Biological Chemistry

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Background:The endothelium requires stabilization factors for efficient blood vessel formation. Results: Engulfment and cell motility 1/dedicator of cytokinesis 180 (Elmo1/Dock180) expression reduces endothelial cell apoptosis in vitro and in vivo. Conclusion: Elmo1/Dock180 protects endothelial cells from apoptosis and acts as a stabilization factor for the endothelium. Significance: First report revealing a cell-intrinsic, pro-survival function of Elmo1/Dock180 in the endothelium.

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RAS and RHO Families of GTPases Directly Regulate Distinct Phosphoinositide 3-Kinase Isoforms

Cited by 259 publications

References 50 publications

Truncating PREX2 mutations activate its GEF activity and alter gene expression regulation in NRAS-mutant melanoma

Truncating PREX2 mutations activate its GEF activity and alter gene expression regulation in NRAS-mutant melanoma

PI3K isoform dependence of PTEN-deficient tumors can be altered by the genetic context

The Bipartite Rac1 Guanine Nucleotide Exchange Factor Engulfment and Cell Motility 1/Dedicator of Cytokinesis 180 (Elmo1/Dock180) Protects Endothelial Cells from Apoptosis in Blood Vessel Development

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