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

Bechard, Matthew E.; Trost, Robert; Singh, Arashdeep; Dalton, Stephen

doi:10.1128/mcb.05372-11

Cited by 27 publications

(40 citation statements)

References 22 publications

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“…This includes several types of stem cells, including pluripotent stem cells, [31,[62][63][64][65] HSC, [20,22,[66][67][68] neural stem cells [69][70][71][72][73][74], and epithelial stem cells [75]. A recurring theme in several stem cell types is for the PI3K/Akt pathway to inactivate GSK3b thus promoting activation and nuclear translocation of b-catenin [76,77]. Our studies suggest a similar role for this pathway in MS/PCs that is regulated by SHIP1.…”

Section: Discussionmentioning

confidence: 76%

SHIP1 Regulates MSC Numbers and Their Osteolineage Commitment by Limiting Induction of the PI3K/Akt/β-Catenin/Id2 Axis

Iyer

Viernes

Chisholm³

et al. 2014

Stem Cells and Development

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Here, we show that Src homology 2-domain-containing inositol 5¢-phosphatase 1 (SHIP1) is required for the efficient development of osteoblasts from mesenchymal stem cells (MSCs) such that bone growth and density are reduced in mice that lack SHIP1 expression in MSCs. We find that SHIP1 promotes the osteogenic output of MSCs by limiting activation of the PI3K/Akt/b-catenin pathway required for induction of the MSC stemness factor Id2. In parallel, we demonstrate that mice with myeloid-restricted ablation of SHIP1, including osteoclasts (OCs), show no reduction in bone mass or density. Hence, diminished bone mass and density in the SHIP1-deficient mice results from SHIP deficiency in MSC and osteolineage progenitors. Intriguingly, mice with a SHIP-deficient MSC compartment also exhibit decreased OC numbers. In agreement with our genetic findings we also show that treatment of mice with an SHIP1 inhibitor (SHIPi) significantly reduces bone mass. These findings demonstrate a novel role for SHIP1 in MSC fate determination and bone growth. Further, SHIPi may represent a novel therapeutic approach to limit bone development in osteopetrotic and sclerotic bone diseases.

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Section: Discussionmentioning

confidence: 76%

SHIP1 Regulates MSC Numbers and Their Osteolineage Commitment by Limiting Induction of the PI3K/Akt/β-Catenin/Id2 Axis

Iyer

Viernes

Chisholm³

et al. 2014

Stem Cells and Development

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“…The FRAT1 gene has been demonstrated to be involved in the regulation of β-catenin expression and secretion (14). Previous studies have demonstrated that in non-small cell lung cancer and gastric cancer tissues, overexpression of FRAT1 activates the Wnt signaling pathway and promotes tumor malignancy (15,16). However, few studies have investigated the effect of FRAT1 expression in colon cancer.…”

Section: Introductionmentioning

confidence: 99%

FRAT1 expression regulates proliferation in colon cancer cells

et al. 2016

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Abstract. Colorectal cancer is one of the most common gastric malignancies worldwide. However, the underlying mechanism of colon cancer development and valuable indicators of the disease remain unclear. In this study, the expression of frequently rearranged in advanced T-cell lymphomas 1 (FRAT1) in colon cancer was investigated and the association between FRAT1 expression and biological properties of tumors was analyzed. A total of 147 colon cancer tissue samples and adjacent normal tissues were collected between January 2013 and June 2014. The FRAT1 gene and protein expression levels were analyzed in tissues with different TNM and pathological stages. Small hairpin RNAs (shRNAs) containing the human FRAT1 gene were constructed and transfected into colon cancer HT-29 cells. The proliferation and migration of the cells was also analyzed in relation to a reduction in FRAT1 expression. In colon cancer tissues, the expression of FRAT1 was significantly higher when compared with adjacent tissues. In addition, FRAT1 expression was found to positively correlate with the degree of tumor malignancy, and this difference was determined to be statistically significant (P<0.05). Following shRNA transfection in HT-29 cells to decrease the expression of FRAT1, the proliferation and migration of the HT-29 cells decreased (due to conversion of the shRNA into small interfering RNA). These results indicate that in colon cancer, FRAT1 may present a novel tool for analyzing the tumor progression and may be a novel therapeutic target for the treatment of colon cancer.

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“…In murine cells, Akt directly phosphorylates Gsk3β on serine-9 (S9), keeping it inactive [5][6][7] while also regulating its ability to shuttle in and out of the nucleus and affecting its ability to target substrates such as c-myc. 8,9 Although inhibition of PI3K/Akt signaling in human and murine PSCs results in differentiation, 10,11 its function is subtly different in the naïve and primed states. PI3K/Akt has two roles in primed human PSCs.…”

Section: Introductionmentioning

confidence: 99%

“…In mESCs, inhibition of PI3K/Akt signaling results in Gsk3β activation. [5][6][7][8][9] In human PSCs, however, this results in Erk activation and Gsk3β inactivation. 1 Given these opposite findings, we decided to directly compare the response to PI3K/ Akt inhibition in mouse and human PSCs (Fig.…”

Section: Introductionmentioning

confidence: 99%

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Reconciling the different roles of Gsk3β in “naïve” and “primed” pluripotent stem cells

et al. 2012

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Signaling pathways orchestrated by PI3K/Akt, Raf/Mek/Erk and Wnt/ β-catenin are known to play key roles in the self-renewal and differentiation of pluripotent stem cells. The serine/ threonine protein kinase Gsk3β has roles in all three pathways, making its exact function difficult to decipher. Consequently, conflicting reports have implicated Gsk3β in promoting selfrenewal, while others suggest that it performs roles in the activation of differentiation pathways. Different thresholds of Gsk3β activity also have different biological effects on pluripotent cells, making this situation even more complex. Here, we describe a further level of complexity that is most apparent when comparing "naïve" murine and "primed" human pluripotent stem cells. In naïve cells, Gsk3β activity is restrained by PI3K/Akt, but when released from inhibitory signals it antagonizes selfrenewal pathways by targeting pluripotency factors such as Myc and Nanog. This situation also applies in primed cells, but, in addition, a separate pool of Gsk3β is required to suppress canonical Wnt signaling. These observations suggest that different Gsk3β-protein complexes shift the balance between naïve and primed pluripotent cells and identify fundamental differences in their cell signaling. Altogether, these findings have important implications for the mechanisms underpinning the establishment of different pluripotent cell states and for the control of self-renewal and differentiation.

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

Cited by 27 publications

References 22 publications

SHIP1 Regulates MSC Numbers and Their Osteolineage Commitment by Limiting Induction of the PI3K/Akt/β-Catenin/Id2 Axis

SHIP1 Regulates MSC Numbers and Their Osteolineage Commitment by Limiting Induction of the PI3K/Akt/β-Catenin/Id2 Axis

FRAT1 expression regulates proliferation in colon cancer cells

Reconciling the different roles of Gsk3β in “naïve” and “primed” pluripotent stem cells

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