Frat oncoproteins act at the crossroad of canonical and noncanonical Wnt-signaling pathways

Amerongen, Renée van; Nawijn, Martijn C.; Lambooij, J-P; Proost, Natalie; Jonkers, Jos; Berns, Anton

doi:10.1038/onc.2009.310

Cited by 40 publications

(38 citation statements)

References 46 publications

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“…FRAT1 overexpression is associated with tumorigenesis [127][128][129][130]. Interestingly, FRAT1 is considered to be one of the links between -catenin dependent (canonical) and -catenin independent (non-canonical) Wnt signaling through its activation of JNK and AP-1(activator protein 1) [131].…”

Section: Gsk3mentioning

confidence: 99%

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

Voronkov¹,

Krauß²

2012

CPD

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Wnt/ -catenin signaling is a branch of a functional network that dates back to the first metazoans and it is involved in a broad range of biological systems including stem cells, embryonic development and adult organs. Deregulation of components involved in Wnt/ -catenin signaling has been implicated in a wide spectrum of diseases including a number of cancers and degenerative diseases. The key mediator of Wnt signaling, -catenin, serves several cellular functions. It functions in a dynamic mode at multiple cellular locations, including the plasma membrane, where -catenin contributes to the stabilization of intercellular adhesive complexes, the cytoplasm where -catenin levels are regulated and the nucleus where -catenin is involved in transcriptional regulation and chromatin interactions. Central effectors of -catenin levels are a family of cysteine-rich secreted glycoproteins, known as Wnt morphogens. Through the LRP5/6-Frizzled receptor complex, Wnts regulate the location and activity of the destruction complex and consequently intracellularcatenin levels. However, -catenin levels and their effects on transcriptional programs are also influenced by multiple other factors including hypoxia, inflammation, hepatocyte growth factor-mediated signaling, and the cell adhesion molecule E-cadherin. The broad implications of Wnt/ -catenin signaling in development, in the adult body and in disease render the pathway a prime target for pharmacological research and development. The intricate regulation of -catenin at its various locations provides alternative points for therapeutic interventions.

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Section: Gsk3mentioning

confidence: 99%

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

Voronkov¹,

Krauß²

2012

CPD

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“…Previously, Frat proteins were believed to regulate canonical Wnt signaling as part of vertebrate development, but more recent data indicate they are dispensable (18). Other roles outside this pathway, including Gsk3-independent roles for Frat in the targeting of Jun N-terminal protein kinase (JNK) and Ap-1 for activation, have been recently demonstrated (19). Our studies identified a novel PI3K/Akt-regulated role for Frat that targets the pool of Gsk3␤ regulated by canonical PI3K/Akt signaling.…”

Section: Discussionmentioning

confidence: 99%

Frat Is a Phosphatidylinositol 3-Kinase/Akt-Regulated Determinant of Glycogen Synthase Kinase 3β Subcellular Localization in Pluripotent Cells

Bechard

Trost

Singh

et al. 2012

Molecular and Cellular Biology

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Suppressing the activity of Gsk3␤ is critical for maintenance of murine pluripotent stem cells. In murine embryonic stem cells (mESCs), Gsk3␤ is inhibited by multiple mechanisms, including its inhibitory phosphorylation on serine 9 by protein kinase B (Akt), a major effector of the canonical phosphatidylinositol 3-kinase (PI3K) pathway. A second PI3K/Akt-regulated mechanism promotes the nuclear export of Gsk3␤, thereby restricting its access to nuclear substrates such as c-myc and ␤-catenin. Although Gsk3␤ shuttles between the nucleus and cytoplasm under self-renewing conditions, its localization is primarily cytoplasmic because its rate of nuclear export exceeds its rate of nuclear import. In this report, we show that Gsk3␤ is exported from the nucleus in a complex with Frat. Loss of PI3K/Akt activity results in dissociation of this complex and retention of Gsk3␤ in the nucleus. Frat continues to shuttle between the nucleus and cytoplasm under these conditions and remains predominantly in the cytoplasm. These results indicate that Frat carries Gsk3␤ out of the nucleus under self-renewing conditions and that PI3K regulates this by promoting its association with Frat. These findings provide new links between PI3K/Akt signaling and regulation of Gsk3␤ activity by Frat, an oncogene previously shown to cooperate with Myc in tumorigenesis.

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“…MLL fusions up-regulate expression of Frat1 and Frat2, encoding oncoproteins that differentially promote canonical and noncanonical Wnt signaling, respectively. 35 Inhibition of Frat2 expression results in reduced Rac activity, whereas Frat2 overexpression leads to enhanced activity. These effects are mediated via DVL1 and GSK3, both of which can modulate Rac activation, and sequestration of DVL from GSK3 inhibits Rac activation and the leukemogenic activity of MLL-ENL (Figure 7).…”

Section: Discussionmentioning

confidence: 99%

“…30,31 The FRAT oncoproteins 32,33 can interact with DVL complexes 23,34 and can potentiate both canonical and noncanonical Wnt signaling. 35 Interestingly, elevated expression of FRAT1 has previously been shown to be associated with MLL-rearranged leukemia, 36 whereas Frat2 was found to be a transcriptional target of wild-type MLL. 37 Furthermore, a recent study demonstrated reduction in the expression of Frat2 after shRNA-mediated silencing of the MLL fusion target gene Myb, in leukemic mouse MLL-AF9 cells.…”

Section: Frat Oncoproteins Mediate Rac Activation By Mll Fusionsmentioning

confidence: 99%

Frat2 mediates the oncogenic activation of Rac by MLL fusions

Walf-Vorderwülbecke

Boer

Horton

et al. 2012

Blood

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IntroductionTranslocations affecting the mixed lineage leukemia (MLL) gene on chromosome band 11q23 are the most common chromosomal aberrations in pediatric acute myeloid leukemia (AML). 1 This cytogenetic subgroup is associated with an intermediate risk, 2 intensive chemotherapy having improved overall survival, although MLL-rearranged AML is still unfavorable in older patients. 3 Taken together, these data suggest that novel therapeutic interventions based on targeting MLL fusion function would benefit a significant number of patients.The MLL fusion genes resulting from these translocations are potent oncogenes. [4][5][6] They are sufficient to induce aberrant selfrenewal programs in mouse hematopoietic progenitor cells (HPCs) leading to transformation and leukemic progression. 7,8 Recent studies have demonstrated that this is also true for human HPCs. 9,10 We and others have previously shown that inhibition of MLL fusion expression reverses HPC immortalization [11][12][13] and abrogates established leukemia in vivo. 14,15 This suggests that the transcriptional and signaling pathways controlled by MLL fusions are necessary for maintenance as well as initiation of leukemia. Recent studies have demonstrated that progression of preleukemic to leukemic MLL fusion cells involves increased canonical Wnt signaling 16 and Rac GTPase activation 17 ; both of these signaling pathways play critical roles in leukemia progression. 10,16,[18][19][20] The sensitivity of MLL-rearranged AML cells to Rac inhibition suggests that targeting Rac activity or signaling pathways leading to Rac activation may represent novel therapeutic opportunities. In support of this, pharmacologic Rac inhibition was found to interfere with leukemic engraftment of MLL-rearranged human AML cell lines. 19 The available evidence indicates that MLL fusions can induce Rac activity. Thus, transformation of human cord blood-derived HPCs by MLL-AF9 was accompanied by increased Rac activation. 10,19 However, little is known about the molecular details of how this is achieved. In the present study, we have used conditionally immortalized preleukemic and leukemic cells to address the dependency of Rac GTPase activity on continued MLL fusion expression and to establish components of the signaling pathway linking the 2. These experiments identify multiple points potentially suitable for therapeutic targeting of MLL-rearranged AML. Methods MiceAll mice were maintained in the animal facilities of the UCL Institute of Child Health and experiments were performed according to United Kingdom Home Office regulations. The generation and characterization of Frat1/2/3 triple-knockout (TKO) mice have been reported previously. 21 These mice have been backcrossed onto the C57BL/6 background 20 times. Age-and sex-matched C57BL/6 J mice were used as controls. Retrovirus and lentivirus cloning and productionThe pMSCV-MLL-ENL-pgk-neo retroviral construct has been previously described. 14 Oligonucleotides for shRNAs targeting Frat1, Frat2, and Dvl1 were designed using RNAi centra...

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Frat oncoproteins act at the crossroad of canonical and noncanonical Wnt-signaling pathways

Cited by 40 publications

References 46 publications

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

Frat Is a Phosphatidylinositol 3-Kinase/Akt-Regulated Determinant of Glycogen Synthase Kinase 3β Subcellular Localization in Pluripotent Cells

Frat2 mediates the oncogenic activation of Rac by MLL fusions

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